Heteroarylcarboxylic acid ester derivative

ABSTRACT

Compounds represented by the following formula (I); 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification, are useful as hyperglycemic inhibitors having a serine protease inhibitory action and as prophylactic or therapeutic drugs for diabetes.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/JP2013/067015, filed on Jun. 14, 2013, and claims priority toU.S. patent application Ser. No. 13/517,805, filed on Jun. 14, 2012,both of which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds, heteroarylcarboxylicacid ester derivatives, which exhibit a serine protease (particularlytrypsin and enteropeptidase) inhibitory activity. The present inventionalso relates to pharmaceutical compositions which contain such acompound and drugs for the treatment or prophylaxis of diabetes. Thepresent invention further relates to methods for the treatment and/orprophylaxis of diabetes by administering such a heteroarylcarboxylicacid ester derivative.

2. Discussion of the Background

At present, insulin secretagogues (sulfonylureas), glucose absorptioninhibitors (α-glucosidase inhibitors), insulin sensitizers (biguanide,thiazolidine derivatives), and the like are clinically used astherapeutic drugs for diabetes. However, since all of them areaccompanied by side effects such as hypoglycemia, diarrhea, lacticacidosis, edema, and the like; show an insufficient effect; and thelike, a medicament satisfying clinical needs is still needed.

In recent years, a benzoic acid ester having a protease inhibitoryactivity, which is represented by the following compound, has beenreported to show a blood glucose elevation suppressing action in adiabetes animal model (see WO2006/057152, which is incorporated hereinby reference in its entirety). The following compound is considered toshow an enzyme inhibitory activity on trypsin, thrombin, pancreatic, andplasma kallikreins, plasmin and the like and a leukotriene receptorantagonistic action. Moreover, an enteropeptidase inhibitory activity ofthe following compound has also been reported (see Biomedical Research(2001), 22 (5) 257-260, which is incorporated herein by reference in itsentirety). However, many unclear points remain in the relationshipbetween such actions and a blood glucose elevation suppressing action.

On the other hand, as for a heteroarylcarboxylic acid ester structures,JP-A-55-161385, which is incorporated herein by reference in itsentirety, discloses a compound as a therapeutic drug for pancreatitis.In this document, only heteroarylcarboxylic acid ester compounds whereinthe substituent of the heteroarylcarboxylic acid moiety is a methylgroup or a methoxy group or unsubstituted compounds are disclosed, asrepresented by the following formula. While these compounds aredisclosed as showing an inhibitory activity on trypsin, chymotrypsin andthrombin, no description is given as to the enteropeptidase inhibitoryactivity and blood glucose elevation suppressing action.

In addition, Advances in Experimental Medicine and Biology (1989), 247B(Kinins 5, Pt. B), 271-6, which is incorporated herein by reference inits entirety, also describes a heteroarylcarboxylic acid ester having aprotease inhibitory activity, which is represented by the followingformula. However, only compounds wherein the heteroaryl moiety isunsubstituted are disclosed, and no description is given as to theenteropeptidase inhibitory activity and blood glucose elevationsuppressing action of these compounds.

Furthermore, WO99/41231, which is incorporated herein by reference inits entirety, describes a compound represented by the following formula.However, it has a structure wherein an aryl group substituted by acarboxyl group is directly bonded to the heteroaryl moiety, which iscompletely different from the compound of the present invention. Thedocument discloses an inhibitory activity against blood coagulationfactor VIIa; however, no description is given as to the enteropeptidaseinhibitory activity and blood glucose elevation suppressing action.

On the other hand, trypsin is one of the intestinal serine proteases andis produced by degradation of inactive trypsinogen by enteropeptidase.Trypsin is known to activate various digestive enzymes by acting onchymotrypsinogen, proelastase, procarboxylesterase, procolipase andpro-sucrase-isomaltase, and the like. Therefore, it is considered thatan inhibitor of enteropeptidase and trypsin lowers the digestivecapacity for protein, lipid, and carbohydrates, and is effective as adrug for the treatment or prophylaxis of obesity and hyperlipidemia.

WO2006/050999, which is incorporated herein by reference in itsentirety, describes that a medicament that inhibits both enteropeptidaseand trypsin is interesting as a body fat-reducing agent. In addition,WO2009/071601, which is incorporated herein by reference in its entiretyreports a compound which has an inhibitory activity againstenteropeptidase, trypsin, plasmin, kallikrein, and the like as anantiobesity drug. However, neither of these publications describessuppression of blood glucose elevation and hypoglycemic effect affordedby simultaneous inhibition of enteropeptidase and trypsin, and theprotease inhibitor described therein has a structure completelydifferent from that of the compound of the present invention.

Accordingly, there remains a need for compounds which are useful for thetreatment or prophylaxis of diabetes. Therefore, to further satisfy theclinical needs from the aspects of effect, safety and the like, ahyperglycemic inhibitor having a serine protease inhibitory action,which is a new drug for the treatment or prophylaxis of diabetes, isdesired.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompounds which are useful for the treatment or prophylaxis of diabetes.

It is another object of the present invention to provide novel compoundswhich exhibit a serine protease inhibitory action.

It is another object of the present invention to provide novel serineprotease (particularly trypsin and enteropeptidase) inhibitors.

It is another object of the present invention to provide novelintestinal serine protease (particularly trypsin and enteropeptidase)inhibitors.

It is another object of the present invention to provide novelhyperglycemic inhibitors or hypoglycemic agents, and further, drugs forthe treatment and/or prophylaxis of any of diabetes, obesity,hyperlipidemia, diabetic complication, and metabolic syndrome.

It is another object of the present invention to provide novel methodsfor the treatment and/or prophylaxis of any of diabetes, obesity,hyperlipidemia, diabetic complication, and metabolic syndrome.

It is another object of the present invention to provide novel methodsfor improving sensitivity to insulin.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat the heteroarylcarboxylic acid ester derivatives described belowhave serine protease inhibitory activity and are useful for thetreatment and/or prophylaxis of any of diabetes, obesity,hyperlipidemia, diabetic complication, and metabolic syndrome.

Thus, in view of the above-mentioned current situation, the presentinventors have conducted intensive studies and considered thatsimultaneous inhibition of trypsin and enteropeptidase is particularlyeffective for the suppression of blood glucose elevation. They havesynthesized various heteroarylcarboxylic acid ester derivatives, whichare novel compounds, evaluated trypsin and enteropeptidase inhibitoryactivity, and found that certain heteroarylcarboxylic acid esterderivatives are protease inhibitors that simultaneously inhibit them.Furthermore, they have also found that such representative compoundsshow a blood glucose elevation suppressing effect in a diabetes animalmodel.

Accordingly, the present invention provides a compound represented bythe formula (I):

wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³, —NR⁴R⁵ or a group represented by the formula (II):

wherein:

R³ is a hydrogen atom or a C₁₋₄ alkyl group;

R⁴, R⁵ and R⁶ are the same or different and each is independently ahydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group or a C₃₋₈alkenyl group, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded form a C₂₋₉ heterocycle, wherein said C₁₋₈ alkyl group,said carboxyl C₁₋₈ alkyl group, said C₃₋₈ alkenyl group and said C₂₋₉heterocycle may be substituted with one or more substituents;

Ra and Rb are the same or different and each is independently a hydrogenatom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group, a carboxyl group,an aryl group, a C₃₋₆ heterocyclic group containing 1 to 4 heteroatomsselected from the group of O, N and S, or a C₃₋₈ cycloalkyl group, or Raand Rb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, or a C₃₋₉ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, wherein said C₁₋₈ alkyl group,said carboxyl C₁₋₈ alkyl group, said aryl group, said C₃₋₆ heterocyclicgroup, said C₃₋₈ cycloalkyl group, said C₃₋₈ cycloalkane ring and saidC₃₋₉ heterocycle may be substituted with one or more substituents;

Ring A is an arene, a C₃₋₆ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, a C₃₋₈ cycloalkane ring or a C₃₋₈cycloalkene ring, wherein said C₃₋₆ heterocycle, said C₃₋₈ cycloalkanering and said C₃₋₈ cycloalkene ring may be further substituted with anoxo group, in addition to Ya and Yb;

Ya is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a C₁₋₃ alkoxy-carbonyl group, a carboxyl C₁₋₃ alkyl group or asulfo group;

Yb is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a C₁₋₃ alkoxy-carbonyl group, a carboxyl C₁₋₃ alkyl group, anitro group, a cyano group or a C₁₋₃ alkoxyl group;

-   -   p is 0, 1, 2, 3 or 4;    -   q is 0 or 1; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group;

with the proviso that when R¹ and R² are both methyl groups, then X isnot a group represented by the formula:

or a pharmaceutically acceptable salt thereof.

Further, the present invention provides a compound represented by theformula (I):

wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³, —NR⁴R⁵ or a group represented by the formula (II):

wherein:

R³ is a hydrogen atom or a C₁₋₄ alkyl group;

R⁴, R⁵ and R⁶ are the same or different and each is independently ahydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group or a C₃₋₈alkenyl group, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded form a C₃₋₉ heterocycle, wherein said C₁₋₈ alkyl group,said C₃₋₈ alkenyl group and said C₃₋₉ heterocycle may be substitutedwith one or more substituents;

Ra and Rb are the same or different and each is independently a hydrogenatom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group, a carboxyl group,an aryl group, a C₃₋₆ heterocyclic group containing 1 to 4 heteroatomsselected from the group of O, N and S, or a C₃₋₈ cycloalkyl group, or Raand Rb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring or a C₃₋₉ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, wherein said C₁₋₈ alkyl group,said aryl group, said C₃₋₈ cycloalkyl group, said C₃₋₈ cycloalkane ringand said C₃₋₉ heterocycle may be substituted with one or moresubstituents;

Ring A is an arene, a C₃₋₆ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, or a C₃₋₈ cycloalkane ring;

Ya is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a carbonyl group, a carboxyl C₁₋₃ alkyl group or a sulfo group;

Yb is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a carbonyl group, a carboxyl C₁₋₃ alkyl group, a nitro group, acyano group or a C₁₋₃ alkoxyl group;

-   -   p is 0, 1, 2, 3 or 4;    -   q is 0 or 1; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group;

with the proviso that when R¹ and R² are both methyl groups, thenneither of R⁴ nor R⁵ is an ethyl group substituted with two carboxylgroups, and when R¹ and R² are both methyl groups, then the grouprepresented by the formula (II) is not a group represented by theformula:

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is —NR⁴R⁵ or the group representedby the formula (II), wherein R⁴, R⁵ and R⁶ are each independently ahydrogen atom or a C₁₋₈ alkyl group, or a pharmaceutically acceptablesalt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is —NR⁴R⁵, wherein R⁴ and R⁵together with the nitrogen atom to which they are bonded form a C₂₋₉heterocycle substituted by a halogen atom, a carboxyl group, a carboxylC₁₋₃ alkyl group or a hydroxyl group, or a pharmaceutically acceptablesalt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is a m group represented by theformula (II), wherein p=1 or 2, and q=0, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is a group represented by theformula (II), wherein p=0 and q=1, is or a pharmaceutically acceptablesalt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is a group represented by theformula (II), wherein p=1, q=1, and Ra and Rb are the same or differentand each is independently a hydrogen atom or a C₁₋₈ alkyl group, or Raand Rb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, wherein said C₁₋₈ alkyl group and said C₃₋₈cycloalkane ring may substituted with a group selected from a carboxylgroup, a carbamoyl group, a hydroxyl group, a phenyl group and a C₃₋₆cycloalkyl group, or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein R¹ and R² are the same or differentand each is independently a methyl group, an ethyl group or a propylgroup, or R¹ and R² together with the carbon atom to which they arebonded form a cyclobutane ring or a cyclopentane ring, or apharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein R¹ and R² are the same or differentand each is independently a methyl group, an ethyl group or a propylgroup, or R¹ and R² together with the carbon atom to which they arebonded form a cyclobutane ring or a cyclopentane ring, and X is —OH, ora pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is the group represented by theformula (II), wherein q=1, and Ring A is a benzene ring, a pyridinering, a 1,2-dihydropyridine ring, or a C₃₋₆ heterocycle containing 1-4oxygen atoms, wherein said 1,2-dihydropyridine ring and said C₃₋₆heterocycle containing 1-4 oxygen atoms may be further substituted withan oxo group, in addition to Ya and Yb, or a pharmaceutically acceptablesalt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is a group represented by theformula (II), wherein q=1, Ya is a halogen atom, a carboxyl group, acarboxyl C₁₋₃ alkyl group, a hydroxyl group, a sulfo group or a C₁₋₃alkoxy-carbonyl group, and Yb is a hydrogen atom, a halogen atom, acarboxyl group or a hydroxyl group, or a pharmaceutically acceptablesalt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is —NR⁴R⁵, wherein when R⁴ or R⁵has substituent(s), said substituent is selected from a halogen atom, acarboxyl group, a hydroxyl group, a carboxyl alkyl group, a C₃₋₈ alkenylgroup, a carbamoyl group, a phenyl group, an amino group, a sulfo group,a cyano group, a C₃₋₈ cycloalkyl group, and a C₁₋₈ heterocyclic groupcontaining 1 to 4 heteroatoms selected from the group consisting of O, Nand S, or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is a group represented by theformula (II), wherein, when Ra or Rb has substituent(s), saidsubstituent is selected from a carboxyl group, a hydroxyl group, aphenyl group, an amino group, a methylthio group, a sulfanyl group, acarbamoyl group, a guanidino group, a C₃₋₈ cycloalkyl group, and a C₁₋₈heterocyclic group containing 1-4 heteroatoms selected from the groupconsisting of O, N and S, or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein

R⁴ is

(1) a carboxyl C₁₋₈ alkyl group optionally substituted by 1 to 3substituents selected from (a) a hydroxyl group, (b) an aryl group, (c)a C₃₋₈ cycloalkyl group, (d) a carbamoyl group, (e) an amino group, (f)an aryl group optionally substituted by a hydroxyl group, (g) a C₁₋₃alkylcarbamoyl group optionally substituted by a carboxyl group, and (h)a heterocyclic group, or

(2) a C₁₋₈ alkyl group optionally substituted by 1 to 3 substituentsselected from (a) a sulfo group, (b) a cyano group, (c) a C₁₋₈heterocyclic group, and (d) an aryl group optionally substituted by acarboxyl group, and

R⁵ is a hydrogen atom, a C₁₋₃ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group; or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded forma C₂₋₉ heterocycle substituted by 1 to 3 substituents selected from (1)a halogen atom, (2) a hydroxyl group, (3) a carboxyl group, and (4) acarboxyl C₁₋₃ alkyl group;

R⁶ is a hydrogen atom, a C₁₋₃ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group; and

Ra and Rb are the same or different and each is independently

(1) a hydrogen atom,

(2) a C₁₋₈ alkyl group optionally substituted by 1 to 3 substituentsselected from (a) an aryl group, (b) a hydroxyl group, (c) a carbamoylgroup, and (d) a C₁₋₈ heterocyclic group containing 1 to 4 heteroatomsselected from O, N and S,

(3) a carboxyl C₁₋₈ alkyl group,

(4) an aryl group optionally substituted by a hydroxyl group,

(5) a C₃₋₆ heterocyclic group containing 1 to 4 heteroatoms selectedfrom the group of O, N and S, or

(6) a C₃₋₈ cycloalkyl group, or

Ra and Rb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, or a C₃₋₈ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, each of which is optionallysubstituted by an oxo group, or a pharmaceutically acceptable saltthereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is —OR³, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is —OH, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein X is —OH, —NR⁴R⁵ or a grouprepresented by the formula (II), and each of —NR⁴R⁵ and the grouprepresented by the formula (II) has one carboxyl group, or apharmaceutically acceptable salt thereof.

Further, the present invention provides a compound represented by theformula (I), wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³ or —NR⁸R⁹; wherein

R³ is a hydrogen atom or a C₁₋₄ alkyl group;

R⁸ is an optionally substituted C₁₋₈ alkyl group, an optionallysubstituted aryl group, an optionally substituted C₃₋₆ heterocyclicgroup, an optionally substituted C₃₋₈ cycloalkyl group, or an optionallysubstituted C₃₋₈ cycloalkenyl group, and

R⁹ is a hydrogen atom, an optionally substituted C₁₋₈ alkyl group or anoptionally substituted C₃₋₈ alkenyl group; or

R⁸ and R⁹ together with the nitrogen atom to which they are bonded forman optionally substituted C₂₋₈ heterocycle; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group;

with the proviso that when R¹ and R² are both methyl groups, then X isnot a group represented by the formula:

or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein

R⁸ is

(1) a C₁₋₈ alkyl group optionally substituted by 1 to 3 substituentsselected from (a) a carboxyl group, (b) a hydroxyl group, (c) an arylgroup optionally substituted by a carboxyl group or a hydroxyl group,(d) a sulfo group, (e) a C₃₋₈ cycloalkyl group, (f) a carbamoyl group,(g) an amino group, (h) a cyano group, (i) a C₁₋₈ heterocyclic group,and (j) a C₁₋₃ alkylcarbamoyl group optionally substituted by a carboxylgroup,

(2) an aryl group optionally substituted by 1 to 3 substituents selectedfrom (a) a carboxyl group, (b) a hydroxyl group, (c) a C₁₋₃ alkyl groupoptionally substituted by a carboxyl group, (d) a C₁₋₃ alkoxy-carbonylgroup, and (e) a sulfo group,

(3) a C₃₋₆ heterocyclic group optionally substituted by 1 to 3substituents selected from (a) an oxo group, (b) a C₁₋₃ alkoxyl group,and (c) a halogen atom,

(4) a C₃₋₈ cycloalkyl group optionally substituted by a carboxyl group,or

(5) a C₃₋₈ cycloalkenyl group optionally substituted by a carboxylgroup, and

R⁹ is a hydrogen atom, a C₁₋₈ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group, or a C₃₋₆ alkenyl group; or

R⁸ and R⁹ together with the nitrogen atom to which they are bonded forma C₂₋₉ heterocycle optionally substituted by 1 to 3 substituentsselected from (1) a carboxyl group, (2) a C₁₋₃ alkyl group optionallysubstituted by a carboxyl group, (3) a halogen atom, and (4) a hydroxylgroup, or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein

X is —OH or —NR^(8′)R^(9′), wherein

R^(8′) is a substituted C₁₋₈ alkyl group, a substituted aryl group, asubstituted C₃₋₆ heterocyclic group, a substituted C₃₋₈ cycloalkylgroup, or a substituted C₃₋₈ cycloalkenyl group, each of which has onecarboxyl group, and

R^(9′) is a hydrogen atom, an optionally substituted C₁₋₈ alkyl groupwhich has no carboxyl group, or an optionally substituted C₃₋₈ alkenylgroup which has no carboxyl group; or

R^(8′) and R^(9′) together with the nitrogen atom to which they arebonded form a substituted C₂₋₉ heterocycle which has one carboxyl group,or a pharmaceutically acceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein

R^(8′) is

(1) a C₁₋₈ alkyl group substituted by 1 to 3 substituents selected from(a) a carboxyl group, (b) a hydroxyl group, (c) an aryl group optionallysubstituted by a carboxyl group or a hydroxyl group, (d) a sulfo group,(e) a C₃₋₈ cycloalkyl group, (f) a carbamoyl group, (g) an amino group,(h) a cyano group, (i) a C₁₋₈ heterocyclic group, and (j) a C₁₋₃alkylcarbamoyl group optionally substituted by a carboxyl group,provided that said substituted C₁₋₈ alkyl group has one carboxyl group,

(2) an aryl group substituted by 1 to 3 substituents selected from (a) acarboxyl group, (b) a hydroxyl group, (c) a C₁₋₃ alkyl group optionallysubstituted by a carboxyl group, (d) a C₁₋₃ alkoxy-carbonyl group, and(e) a sulfo group, provided that said substituted aryl group has onecarboxyl group,

(3) a C₃₋₈ cycloalkyl group substituted by one carboxyl group, or

(4) a C₃₋₈ cycloalkenyl group substituted by one carboxyl group, and

R^(9′) is a hydrogen atom, a C₁₋₈ alkyl group optionally substituted bya C₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group;

or

R^(8′) and R^(9′) together with the nitrogen atom to which they is arebonded form a C₂₋₉ heterocycle substituted by 1 to 3 substituentsselected from (1) a carboxyl group, (2) a C₁₋₃ alkyl group optionallysubstituted by a carboxyl group, (3) a halogen atom, and (4) a hydroxylgroup, provided that said substituted C₂₋₉ heterocycle formed by R^(8′)and R^(9′) has one carboxyl group, or a pharmaceutically acceptable saltthereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein R¹ and R² are the same or differentand each is independently a C₁₋₃ alkyl group, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides a compound represented by theaforementioned formula (I), wherein R⁷ is a halogen atom, or apharmaceutically acceptable salt thereof.

Further, the present invention provides a compound represented by any ofthe following formulae:

or a pharmaceutically acceptable salt of said compound.

Further, the present invention provides a compound represented by any ofthe following formulae:

or a pharmaceutically acceptable salt of said compound.

Further, the present invention provides a pharmaceutical composition,comprising the above-mentioned compound or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable carrier orexcipient.

Further, the present invention provides a pharmaceutical compositioncomprising the above-mentioned compound, or a pharmaceuticallyacceptable salt thereof as an active ingredient.

The present invention also provides a method of inhibiting serineprotease, comprising administering an effective amount of theabove-mentioned compound or a pharmaceutically acceptable salt thereofto a subject in need thereof.

The present invention also provides a method of inhibiting intestinalserine protease, comprising administering an effective amount of theabove-mentioned compound or a pharmaceutically acceptable salt thereofto a subject in need thereof.

The present invention also provides a method for inhibiting trypsin andenteropeptidase, comprising administering an effective amount of theabove-mentioned compound or a pharmaceutically acceptable salt thereofto a subject in need thereof.

The present invention also provides a method for treating hyperglycemia,comprising administering an effective amount of the above-mentionedcompound or a pharmaceutically acceptable salt thereof to a subject inneed thereof.

The present invention also provides a method for prophylaxis ortreatment of diabetes, comprising administering an effective amount ofthe above-mentioned compound or a pharmaceutically acceptable saltthereof to a subject in need thereof.

The present invention also provides a method for improving sensitivityto insulin, comprising administering an effective amount of theabove-mentioned compound or a pharmaceutically acceptable salt thereofto a subject in need thereof.

The present invention also provides a method for prophylaxis ortreatment of obesity, hyperlipidemia, a diabetic complication ormetabolic syndrome, comprising administering an effective amount of theabove-mentioned compound or a pharmaceutically acceptable salt thereofto a subject in need thereof.

The present invention also provides an intestinal serine proteaseinhibitor, comprising the above-mentioned compound, or apharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a dual inhibitor of trypsin andenteropeptidase, comprising the above-mentioned compound, or apharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a hyperglycemic inhibitor orhypoglycemic agent, comprising the above-mentioned compound, or apharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a prophylactic or therapeutic drugfor diabetes, comprising the above-mentioned compound, or apharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides an insulin sensitizer comprising theabove-mentioned compound, or a pharmaceutically acceptable salt thereofas an active ingredient.

The present invention also provides a prophylactic or therapeutic drugfor obesity, hyperlipidemia, diabetic complication or metabolicsyndrome, comprising the above-mentioned compound, or a pharmaceuticallyacceptable salt thereof as an active ingredient.

The present invention also provides use of the above-mentioned compound,or a pharmaceutically acceptable salt thereof for the prophylaxis ortreatment of diabetes.

The present invention also provides use of the above-mentioned compound,or a pharmaceutically acceptable salt thereof for the improvement ofinsulin resistance.

The present invention also provides use of the above-mentioned compound,or a pharmaceutically acceptable salt thereof for the prophylaxis ortreatment of obesity, hyperlipidemia, diabetic complication or metabolicsyndrome.

The present invention also provides a method for treating hyperglycemiaor diabetes, comprising administering an effective amount of a compoundrepresented by formula (I):

wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³, —NR⁴R⁵ or a group represented by formula (II):

wherein:

R³ is a hydrogen atom or a C₁₋₄ alkyl group;

R⁴, R⁵ and R⁶ are the same or different and each is independently ahydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group or a C₃₋₈alkenyl group, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded form a C₃₋₉ heterocycle, wherein said C₁₋₈ alkyl group,said C₃₋₈ alkenyl group and said C₃₋₉ heterocycle may be substitutedwith one or more substituents;

Ra and Rb are the same or different and each is independently a hydrogenatom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group, a carboxyl group,an aryl group, a C₃₋₆ heterocyclic group containing 1 to 4 heteroatomsselected from the group consisting of O, N and S, or a C₃₋₈ cycloalkylgroup, or Ra and Rb together with the atom(s) to which they are bondedform a C₃₋₈ cycloalkane ring or a C₃₋₉ heterocycle containing 1-4heteroatoms selected from the group consisting of O, N and S, whereinsaid C₁₋₈ alkyl group, said aryl group, said C₃₋₈ cycloalkyl group, saidC₃₋₈ cycloalkane ring and said C₃₋₉ heterocycle may be substituted withone or more substituents;

Ring A is an arene, a C₃₋₆ heterocycle containing 1-4 heteroatomsselected from the group consisting of O, N and S, or a C₃₋₈ cycloalkanering;

Ya is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a carbonyl group, a carboxyl C₁₋₃ alkyl group or a sulfo group;

Yb is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a carbonyl group, a carboxyl C₁₋₃ alkyl group, a nitro group, acyano group or a C₁₋₃ alkoxyl group;

-   -   p is 0, 1, 2, 3 or 4;    -   q is 0 or 1; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group;

with the proviso that when R¹ and R² are both methyl groups, thenneither of R⁴ nor R⁵ is an ethyl group substituted with two carboxylgroups, and when R¹ and R² are both methyl groups, then the grouprepresented by formula (II) is not a group represented by formula:

or a pharmaceutically acceptable salt thereof,

to a subject in need thereof.

The present invention also provides the above-mentioned method, whereinX is —NR⁴R⁵ or a group represented by formula (II), wherein R⁴, R⁵ andR⁶ are each independently a hydrogen atom or a C₁₋₈ alkyl group.

The present invention also provides the above-mentioned method, whereinX is —NR⁴R⁵, wherein R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded form a C₃₋₉ heterocycle substituted by a hydrogen atom,a halogen atom, a carboxyl group, a carboxyl C₁₋₃ alkyl group or ahydroxyl group.

The present invention also provides the above-mentioned method, whereinX is a group represented by formula (II), wherein p=1 or 2, and q=0.

The present invention also provides the above-mentioned method, whereinX is a group represented by formula (II), wherein p=0 and q=1.

The present invention also provides the above-mentioned method, whereinX is a group represented by formula (II), wherein p=1, q=1, and Ra andRb are the same or different and each is independently a hydrogen atomor a C₁₋₈ alkyl group, or Ra and Rb together with the atom(s) to whichthey are bonded form a C₃₋₈ cycloalkane ring, wherein said C₁₋₈ alkylgroup and said C₃₋₈ cycloalkane ring may substituted with a groupselected from the group consisting of a hydrogen atom, a carboxyl group,a carbamoyl group, a hydroxyl group, a phenyl group and a C₃₋₈cycloalkyl group.

The present invention also provides the above-mentioned method, whereinR¹ and R² are the same or different and each is independently a methylgroup, an ethyl group or a propyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a cyclobutane ring or acyclopentane ring.

The present invention also provides the above-mentioned method, whereinX is a group represented by formula (II), wherein q=1, and Ring A is abenzene ring, a pyridine ring, or a C₁₋₆ heterocycle containing 1-4oxygen atoms.

The present invention also provides the above-mentioned method, whereinX is a group represented by formula (II), wherein q=1, Ya is a halogenatom, a carboxyl group, a carboxyl C₁₋₃ alkyl group, a hydroxyl group, asulfo group or a carbonyl group, and Yb is a hydrogen atom, a halogenatom, a carboxyl group or a hydroxyl group.

The present invention also provides the above-mentioned method, whereinX is —NR⁴R⁵, wherein when R⁴ or R⁵ has substituent(s), said substituentis selected from the group consisting of a halogen atom, a carboxylgroup, a hydroxyl group, a carboxyl C₁₋₃ alkyl group, a C₃₋₈ alkenylgroup, a carbamoyl group, a phenyl group, an amino group, a sulfo group,a cyano group, a C₃₋₈ cycloalkyl group, and a C₁₋₈ heterocyclic groupcontaining 1 to 4 heteroatoms selected from the group consisting of O, Nand S.

The present invention also provides the above-mentioned method, whereinX is a group represented by formula (II), wherein, when Ra or Rb hassubstituent(s), said substituent is selected from the group consistingof a carboxyl group, a hydroxyl group, a phenyl group, an amino group, amethylthio group, a thiol group, a carbamoyl group, a guanidino group, aC₃₋₈ cycloalkyl group, and a C₁₋₈ heterocyclic group containing 1-4heteroatoms selected from the group consisting of O, N and S.

The present invention also provides the above-mentioned method, wherein,said compound represented by formula (I) is a compound represented byany of the following formulae:

The present invention also provides the above-mentioned method, whereinsaid compound represented by formula (I) is a compound represented byany of the following formulae:

The compound of the present invention has a blood glucose elevationsuppressing action and can be preferably used as a drug for thetreatment or prophylaxis of diabetes.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same become betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 shows blood glucose levels at 0, 2, 4, and 8 hours after dosingcompounds of No. 10 and 87, and the vehicle at the dose of 3 mg/kg inKK-A^(y)/JCL mice.

FIG. 2 shows blood glucose levels at 0, 2, 4, and 8 hours after dosingcompounds of No. 19 and 69, and the vehicle at the dose of 3 mg/kg inKK-A^(y)/JCL mice.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is explained in detail in the following.

In the present specification, the phrase “may be substituted” or“optionally having substituent(s)” means “being substituted orunsubstituted”. Unless otherwise specified, the position and number ofthe substituents may be any, and are not particularly limited. Whensubstituted by two or more substituents, the substituents may be thesame or different. Examples of the substituent include a nitro group, ahalogen atom, a cyano group, a hydroxyl group, a sulfanyl group, anamino group, a guanidino group, a formyl group, a phenyl group, a loweralkyl group, a lower alkenyl group, a lower alkynyl group, a lower acylgroup, a carboxyl group, a sulfo group, a phosphono group, a loweralkoxyl group, a lower alkylthio group, a lower alkylamino group, alower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoylgroup, a lower alkylsulfonylamino group, a sulfamoyl group and the like.

In the present specification, examples of the substituent of the “arylgroup optionally having substituent(s)” and “heterocyclic groupoptionally having substituent(s)” include a nitro group, a halogen atom,a cyano group, a hydroxyl group, a sulfanyl group, an amino group, aguanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group and the like.

The “cyclic amino group” in the present specification is a saturated orunsaturated cyclic amino group having a carbon number of 2 to 7, whichmay contain one or more hetero atoms in the ring, such as a nitrogenatom, an oxygen atom, a sulfur atom and the like. For example, apyrrolidinyl group, a pyrrolinyl group, a piperidyl group, a morpholinylgroup, a piperazinyl group, a thiomorpholinyl group, a piperidinonylgroup, a piperazinonyl group and the like can be mentioned.

The term “lower” in, for example, a lower alkyl group in the presentspecification indicates that the group has 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms, and more preferably, 1 to 3 carbonatoms, unless otherwise specified.

The “alkyl group” is a linear or branched or cyclic alkyl group (inparticular, a linear or branched alkyl group), preferably, having acarbon number of 1 to 10, more preferably, having a carbon number of 1to 8 (i.e., the “C₁₋₈ alkyl”). For example, a methyl group, an ethylgroup, an n-propyl group, an n-butyl group, an n-pentyl group, ann-hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group,a tert-butyl group, an isopentyl group, a tert-pentyl group, a neopentylgroup, a 2-pentyl group, a 3-pentyl group, a 2-hexyl group, acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup and the like can be mentioned. Examples of the “C₁₋₄ alkyl group”include an alkyl group with 1 to 4 carbon atoms, from among theabove-mentioned alkyl group. Examples of the “C₁₋₃ alkyl group” includean alkyl group with 1 to 3 carbon atoms, from among the above-mentionedalkyl group. Examples of the “C₃₋₄ alkyl group” include an alkyl groupwith 3 or 4 carbon atoms, from among the above-mentioned alkyl group.

The “carboxyl C₁₋₈ alkyl group” is the C₁₋₈ alkyl substituted by one ormore (e.g., 1 to 3, preferably 1 or 2, more preferably one) carboxylgroups. The “carboxyl C₁₋₃ alkyl” is the C₁₋₃ alkyl group substituted byone or more (e.g., 1 to 3, preferably 1 or 2, more preferably one)carboxyl groups.

The “cycloalkyl group” is a cyclic alkyl group, preferably, having acarbon number of 3 to 10. Examples of the “cycloalkyl” include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup and the like. Examples of the “C₃₋₈ cycloalkyl group” include acycloalkyl group with 3 to 8 carbon atoms, from among theabove-mentioned cycloalkyl group.

The “cycloalkane ring” is a ring moiety in a cycloalkyl group,preferably, having a carbon number of 3 to 10. Examples of the“cycloalkane ring” include a cyclopropane ring, a cyclobutane ring, acyclopentane ring, a cyclohexane ring and the like. Examples of the“C₃₋₈ cycloalkane ring” include a cycloalkane ring with 3 to 8 carbonatoms, from among the above-mentioned cycloalkane ring. Examples of the“C₃₋₅ cycloalkane ring” include a cycloalkane ring with 3 to 5 carbonatoms, from among the above-mentioned cycloalkane ring.

The “alkenyl group” is a linear or branched alkenyl group, preferably,having a carbon number of 2 to 10, which includes each isomer. Forexample, a vinyl group, an allyl group, a propenyl group, a butenylgroup, a pentenyl group, a hexenyl group and the like can be mentioned.Examples of the “C₃₋₈ alkenyl group” include an alkenyl group with 3 to8 carbon atoms, from among the above-mentioned alkenyl group. Examplesof the “C₂₋₄ alkenyl group” include an alkenyl group with 2 to 4 carbonatoms, from among the above-mentioned alkenyl group.

The “cycloalkenyl group” is a cyclic alkenyl group preferably, having acarbon number of 3 to 10. For example, a cyclopropenyl group, acyclobutenyl group a cyclopentenyl group, a cyclohexenyl group and thelike can be mentioned. Examples of the “C₃₋₈ cycloalkenyl group” includea cycloalkenyl group with 3 to 8 carbon atoms, from among theabove-mentioned cycloalkenyl group.

The “C₃₋₈ cycloalkene ring” is a ring moiety in a cyclic alkenyl grouphaving a carbon number of 3 to 8. For example, a cyclopropene ring, acyclobutene ring, a cyclopentene ring, a cyclohexene ring and the likecan be mentioned.

The “alkynyl group” is a linear or branched alkynyl group having acarbon number of 2 to 10, which includes each isomer. For example, anethynyl group, a 1-propynyl group, a 2-propynyl group, a 2-butynylgroup, a 3-butynyl group, a pentynyl group and the like can bementioned.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom,a bromine atom, an iodine atom and the like.

The “acyl group” is an acyl group having a linear or branched or cyclicalkyl group or alkenyl group having a carbon number of 1 to 10,preferably, 1 to 8, more preferably, 1 to 6. For example, an acetylgroup, a propionyl group, a butyryl group, an isobutyryl group, avaleryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group,an acryloyl group, a methacryloyl group, a crotonoyl group, anisocrotonoyl group, a cyclopropanoyl group, a cyclobutanoyl group, acyclopentanoyl group, a cyclohexanoyl group and the like can bementioned.

The “alkoxyl group” is an alkoxyl group having a linear or branched orcyclic alkyl group having a carbon number of 1 to 10, preferably, 1 to8, more preferably, 1 to 6, and further more preferably 1 to 3 (i.e.,the “C₁₋₃ alkoxyl group”). For example, a methoxy group, an ethoxygroup, an n-propoxy group, an n-butoxy group, an n-pentyloxy group, ann-hexyloxy group, an isopropoxy group, an isobutoxy group, a sec-butoxygroup, a tert-butoxy group, a cyclopropyloxy group, a cyclobutyloxygroup, a cyclopentyloxy group and a cyclohexyloxy group can bementioned. Examples of “C₁₋₃ alkoxyl group” include an alkoxyl groupwith 1 to 3 carbon atoms, from among the above-mentioned alkoxyl group.

The “alkylthio group” is an alkylthio group having a linear or branchedor cyclic alkyl group having a carbon number of 1 to 10, preferably, 1to 8, more preferably, 1 to 6. For example, a methylthio group, anethylthio group, an n-propylthio group, an isopropylthio group, ann-butylthio group, an isobutylthio group, a sec-butylthio group, atert-butylthio group, a cyclopropylthio group, a cyclobutylthio group, acyclopentylthio group, a cyclobutylthio group and the like can bementioned.

The “alkylamino group” is an amino group mono- or di-substituted by theaforementioned “alkyl group”, preferably, “lower alkyl group”. Forexample, a methylamino group, an ethylamino group, a propylamino group,an isopropylamino group, a dimethylamino group, a diethylamino group, adipropylamino group, a diisopropylamino group, an ethylmethylamino groupand the like can be mentioned.

The “acyloxy group” is a group wherein an oxygen atom is bonded to thecarbon of the carbonyl moiety of the aforementioned “acyl group”,preferably, “lower acyl group”. For example, an acetyloxy group, apropionyloxy group, a butyryloxy group, an isobutyryloxy group, avaleryloxy group, an isovaleryloxy group, a pivaloyloxy group, ahexanoyloxy group, an acryloyloxy group, a methacryloyloxy group, acrotonoyloxy group, an isocrotonoyloxy group and the like can bementioned.

The “acylamino group” is a group wherein a nitrogen atom is bonded tothe carbon of the carbonyl moiety of the aforementioned “acyl group”,preferably, “lower acyl group”. For example, an acetylamino group, apropionylamino group, a butyrylamino group, an isobutyrylamino group, avalerylamino group, an isovalerylamino group, a pivaloylamino group, ahexanoylamino group, an acryloylamino group, a methacryloylamino group,a crotonoylamino group, an isocrotonoylamino group and the like can bementioned.

The “alkoxycarbonyl group” is a carbonyl group having the aforementioned“alkoxyl group”, preferably, “lower alkoxyl group” such as C₁₋₃ alkoxylgroup For example, a methoxycarbonyl group, an ethoxycarbonyl group, apropoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonylgroup, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group and the like can be mentioned. Examples of the“C₁₋₃ alkoxy-carbonyl group” include a carbonyl group with theabove-mentioned C₁₋₃ alkoxyl group, from among the above-mentionedalkoxycarbonyl group.

The “alkylcarbamoyl group” is a group wherein a nitrogen atom of theaforementioned “alkylamino group” or “cyclic amino group”, and a carbonatom of the carbonyl group are bonded. For example, an N-methylcarbamoylgroup, an N-ethylcarbamoyl group, an N,N-dimethylcarbamoyl group, a1-pyrrolidinylcarbonyl group, a 1-piperidylcarbonyl group, a4-morpholinylcarbonyl group, and the like can be mentioned. Examples ofthe “C₁₋₃ alkyl-carbamoyl group” include an alkylcarbamoyl group with 1to 3 carbon atoms in the “alkylamino group” or the “cyclic amino group”,from among the above-mentioned alkylcarbamoyl group.

The “alkylsulfonylamino group” is a group wherein a nitrogen atom isbonded to a sulfonyl group wherein the aforementioned “alkyl group”,preferably, “lower alkyl group” is bonded to a sulfur atom. For example,a methylsulfonylamino group, an ethylsulfonylamino group, apropylsulfonylamino group, an isopropylsulfonylamino group, abutylsulfonylamino group, an isobutylsulfonylamino group and the likecan be mentioned.

The “arylsulfonylamino group” is a group wherein a nitrogen atom isbonded to a sulfur atom of a sulfonyl group substituted by an arylgroup. For example, a phenylsulfonylamino group, a naphthylsulfonylaminogroup and the like can be mentioned.

Examples of the “aryl group” include an aryl group having a carbonnumber of 6 to 14 such as a phenyl group, a naphthyl group and the like,preferably, a phenyl group.

The “arene” is a ring moiety in the aryl group having a carbon number of6 to 14. Examples of “arene” include a benzene ring, a naphthalene ringand the like, preferably, a benzene ring.

The “heterocyclic group” is a 3- to 14-membered monocyclic to tricyclicheterocyclic group containing, as a ring atom, 1 to 4 hetero atomsselected from an oxygen atom, a sulfur atom and a nitrogen atom. Anycarbon atom as a ring atom may be substituted by an oxo group, and asulfur atom or a nitrogen atom may be oxidized to form an oxide. Inaddition, it may be condensed with a benzene ring. For example, apyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinylgroup, a furyl group, a thienyl group, a pyrrolyl group, an isoxazolylgroup, an oxazolyl group, an isothiazolyl group, a thiazolyl group, apyrazolyl group, an imidazolyl group, an oxadiazolyl group, athiadiazolyl group, a triazolyl group, a tetrazolyl group, abenzofuranyl group, a benzothienyl group, an indolyl group, anisoindolyl group, a benzoxazolyl group (=a benzooxazolyl group), abenzothiazolyl group, a benzimidazolyl group (=a benzoimidazolyl group),an indazolyl group, a benzisoxazolyl group, a benzisothiazolyl group, abenzofurazanyl group, a benzothiadiazolyl group, a purinyl group, aquinolinyl group, an isoquinolyl group, a cinnolinyl group, aphthalazinyl group, a quinazolinyl group, a quinoxalinyl group, apteridinyl group, an imidazooxazolyl group, an imidazothiazolyl group,an imidazoimidazolyl group, a dibenzofuryl group, a dibenzothienylgroup, a carbazolyl group, an acridinyl group, a pyrrolidinyl group, apyrazolidinyl group, an imidazolidinyl group, a pyrrolinyl group, apyrazolinyl group, an imidazolinyl group, a tetrahydrofuryl group, atetrahydrothiophenyl group, a thiazolidinyl group, a piperidyl group, apiperazinyl group, a quinuclidinyl group, a tetrahydropyranyl group, atetrahydrothiopyranyl group, a morpholinyl group, a thiomorpholinylgroup, a dioxolanyl group, a homopiperidyl group, a homopiperazinylgroup, an indolinyl group, an isoindolinyl group, a chromanyl group, anisochromanyl group, a tetrahydronaphthyridinyl group, an azaindolylgroup, a tetrahydroisoquinolinyl group, an aziridinyl group, anazetidinyl group, a dihydropyridyl group and the like can be mentioned.Preferably, a thiadiazolyl group, an imidazolyl group, a 1H-tetrazolylgroup, a piperidyl group, a piperazinyl group, a thiazolidinyl group, atetrahydroisoquinolinyl group, an aziridinyl group, an azetidinyl group,a tetrahydrofuryl group, a dihydropyridyl group and the like can bementioned. Examples of the “C₃₋₈ heterocyclic group” include aheterocyclic group with 3 to 8 carbon atoms as a ring atom, from amongthe above-mentioned heterocyclic group. Examples of the “C₃₋₆heterocyclic group” include a heterocyclic group with 3 to 6 carbonatoms as a ring atom, from among the above-mentioned heterocyclic group.Examples of the “C₁₋₈ heterocyclic group” include a heterocyclic groupwith 1 to 8 carbon atoms as a ring atom, from among the above-mentionedheterocyclic group.

The “heterocycle” is a 3- to 14-membered monocyclic to tricyclicheterocycle containing, as a ring atom, 1 to 4 hetero atoms selectedfrom an oxygen atom, a sulfur atom and a nitrogen atom. Any carbon atomas a ring atom may be substituted by an oxo group, and a sulfur atom ora nitrogen atom may be oxidized to form an oxide. In addition, it may becondensed with a benzene ring. For example, a pyridine ring, apyridazine ring, a pyrimidine ring, a pyrazine ring, a furan ring, athiophene ring, a pyrrole ring, an isoxazole ring, an oxazole ring, anisothiazole ring, a thiazole ring, a pyrazole ring, an imidazole ring,an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazolering, a benzofuran ring, a benzothiophene ring, an indole ring, anisoindole ring, a benzoxazole ring (=a benzooxazole ring), abenzothiazole ring, a benzimidazole ring (=a benzoimidazole ring), anindazole ring, a benzisoxazole ring, a benzisothiazole ring, abenzofurazane ring, a benzothiadiazole ring, a purine ring, a quinolinering, an isoquinoline ring, a cinnoline ring, a phthalazine ring, aquinazoline ring, a quinoxaline ring, a pteridine ring, animidazooxazole ring, an imidazothiazole ring, an imidazoimidazole ring,a dibenzofuran ring, a dibenzothiophene ring, a carbazole ring, anacridine ring, a pyrrolidine ring, a pyrazolidine ring, an imidazolidinering, a pyrroline ring, a pyrazoline ring, an imidazoline ring, atetrahydrofuran ring, a tetrahydrothiophene ring, a thiazolidine ring, apiperidine ring, a piperazine ring, a quinuclidine ring, atetrahydropyrane ring, a tetrahydrothiopyrane ring, a morpholine ring, athiomorpholine ring, a dioxolane ring, a homopiperidine ring, ahomopiperazine ring, an indoline ring, an isoindoline ring, a chromanering, an isochromane ring, a tetrahydronaphthyridine ring, an azaindolering, a tetrahydroisoquinoline ring, an aziridine ring, an azetidinering, a dihydropyridine ring and the like can be mentioned. Preferably,a thiadiazole ring, an imidazole ring, a tetrazole ring, a piperidinering, a piperazine ring, a thiazolidine ring, a tetrahydroisoquinolinering, an aziridine ring, an azetidine ring, a tetrahydrofuran ring, adihydropyridine ring and the like can be mentioned. Examples of the“C₂₋₉ heterocycle” include a heterocycle with 2 to 9 carbon atoms as aring atom, from among the above-mentioned heterocycle. Examples of the“C₃₋₉ heterocycle” include a heterocycle with 3 to 9 carbon atoms as aring atom, from among the above-mentioned heterocycle. Examples of the“C₃₋₆ heterocycle” include a heterocycle with 3 to 6 carbon atoms as aring atom, from among the above-mentioned heterocycle. Examples of the“C₁₋₆ heterocycle” include a heterocycle with 1 to 6 carbon atoms as aring atom, from among the above-mentioned heterocycle.

The “serine protease” in the present specification is a protease having,as a catalytic residue, a serine residue having nucleophilicity. Forexample, trypsin, chymotrypsin, elastase, enteropeptidase, kallikrein,thrombin, factor Xa, and tryptase, and the like can be mentioned. Inaddition, the term “serine protease inhibition” in the presentspecification means a decrease or disappearance of the aforementionedserine protease activity. Preferably, it is an inhibition of theactivity of intestinal serine proteases such as trypsin,enteropeptidase, chymotrypsin, elastase and the like, particularlypreferably inhibition of trypsin and enteropeptidase activities.

The serine protease inhibitor of the present invention is a dualinhibitor that simultaneously inhibits at least trypsin andenteropeptidase.

The diabetes in the present specification means type I diabetes mellitusand type II diabetes mellitus, with preference given to type II diabetesmellitus.

In the present invention, the compound represented by the formula (I) ora pharmaceutically acceptable salt thereof is preferably as follows.

In the formula (I), R¹ and R² are the same or different and each isindependently a C₁₋₄ alkyl group or a C₂₋₄ alkenyl group, or R¹ and R²together with the carbon atom to which they are bonded form a C₃₋₈cycloalkane ring. Preferably, R¹ and R² are the same or different fromeach other and each is independently a linear or branched C₁₋₄ alkylgroup (specifically, a methyl group, an ethyl group and the like), or R¹and R² together with the carbon atom to which they are bonded form aC₃₋₅ cycloalkane ring (specifically, a cyclobutane ring, a cyclopentanering and the like). More preferably R¹ and R² are independently a C₁₋₃alkyl group (specifically, a methyl group, an ethyl group and the like),particularly extremely preferably a methyl group and an ethyl group andthe like.

In other aspect, it is also preferable that R¹ and R² are the same.

In other aspect, R¹ and R² are, preferably, both a methyl group or anethyl group. In other aspect, R¹ and R² are, preferably, both methylgroups. In other aspect, R¹ and R² are, preferably, both ethyl groups.

In other aspect, R¹ and R² are, preferably, the same or different andeach is independently a methyl group, an ethyl group or a propyl group,or R¹ and R² together with the carbon atom to which they are bonded forma cyclobutane ring or a cyclopentane ring.

In the formula (I), X is —OR³, —NR⁴R⁵ or a group represented by theformula (II):

preferably, —NR⁴R⁵ or a group represented by the formula (II), morepreferably, a group represented by the formula (II). In other aspect, Xis more preferably —NR⁴R⁵. In other aspect, X is preferably —OR³, morepreferably —OH.

In other aspect, X is preferably —OH, —NR⁴R⁵ or a group represented bythe formula (II), and each of —NR⁴R⁵ and the group represented by theformula (II) has one carboxyl group, particularly, X is —OH, from theaspect of stability and few side effects.

In the group —OR³, R³ is a hydrogen atom or a C₁₋₄ alkyl group,preferably a hydrogen atom (i.e., —OR³ is preferably —OH).

In the group —NR⁴R⁵, R⁴ and R⁵ are the same or different and each isindependently a hydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkylgroup or a C₃₋₈ alkenyl group, or R⁴ and R⁵ together with the nitrogenatom to which they are bonded form a C₃₋₉ heterocycle, wherein said C₁₋₈alkyl group, said C₃₋₈ alkenyl group and said C₃₋₉ heterocycle may besubstituted with one or more substituents.

In other aspect, in the group —NR⁴R⁵, R⁴ and R⁵ are the same ordifferent and each is independently a hydrogen atom, a C₁₋₈ alkyl group,a carboxyl C₁₋₈ alkyl group or a C₃₋₈ alkenyl group, or R⁴ and R⁵together with the nitrogen atom to which they are bonded form a C₂₋₉heterocycle, wherein said C₁₋₈ alkyl group, said carboxyl C₁₋₈ alkylgroup, said C₃₋₈ alkenyl group and said C₂₋₉ heterocycle may besubstituted with one or more substituents.

Preferably R⁴ and R⁵ are the same or different and each is independentlya hydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkyl group or aC₃₋₈ alkenyl group, wherein said C₁₋₈ alkyl group, said carboxyl C₁₋₈alkyl group and said C₃₋₈ alkenyl group may be substituted with one ormore substituents.

More preferably, R⁴ and R⁵ are the same or different and each isindependently a hydrogen atom, a C₁₋₃ alkyl group or a carboxyl C₁₋₃alkyl group, wherein said C₁₋₃ alkyl group and said carboxyl C₁₋₃ alkylgroup may be substituted with one or more substituents.

In other aspect, preferably,

R⁴ is

(1) a carboxyl C₁₋₈ alkyl group optionally substituted by 1 to 3substituents selected from

-   -   (a) a hydroxyl group,    -   (b) an aryl group (specifically, a phenyl group and the like),    -   (c) a C₃₋₈ cycloalkyl group (specifically, a cyclohexyl group        and the like),    -   (d) a carbamoyl group,    -   (e) an amino group,    -   (f) an aryl group (specifically, a phenyl group and the like)        optionally substituted by a hydroxyl group,    -   (g) a C₁₋₃ alkyl-carbamoyl group (specifically, an        N-methylcarbamoyl group and the like) optionally substituted by        a carboxyl group, and    -   (h) a C₁₋₈ heterocyclic group (specifically, a 1H-tetrazolyl        group and the like), or

(2) a C₁₋₈ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a sulfo group,    -   (b) a cyano group,    -   (c) a C₁₋₈ heterocyclic group (specifically, a 1H-tetrazolyl        group and the like), and    -   (d) an aryl group (specifically, a phenyl group and the like)        optionally substituted by a carboxyl group, and

R⁵ is a hydrogen atom, a C₁₋₃ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group (specifically, a cyclopropyl group and the like),or a C₃₋₈ alkenyl group; or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded forma C₂₋₉ heterocycle substituted by 1 to 3 substituents selected from

-   -   (1) a halogen atom (specifically, a fluorine atom and the like),    -   (2) a hydroxyl group,    -   (3) a carboxyl group, and    -   (4) a carboxyl C₁₋₃ alkyl group (specifically, a carboxylmethyl        and group the like). More preferably,

R⁴ is

(1) a carboxyl C₁₋₈ alkyl group optionally substituted by 1 to 3substituents selected from

-   -   (a) a hydroxyl group,    -   (b) an aryl group (specifically, a phenyl group and the like),    -   (c) a C₃₋₈ cycloalkyl group (specifically, a cyclohexyl group        and the like),    -   (d) a carbamoyl group,    -   (e) an amino group,    -   (f) an aryl group (specifically, a phenyl group and the like)        optionally substituted by a carboxyl group or a hydroxyl group,    -   (g) a C₁₋₃ alkyl-carbamoyl group (specifically, an        N-methylcarbamoyl group and the like) optionally substituted by        a carboxyl group, and    -   (h) a C₁₋₈ heterocyclic group (specifically, a 1H-tetrazolyl        group and the like), or

(2) a C₁₋₈ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a sulfo group,    -   (b) a cyano group, and    -   (c) a C₁₋₈ heterocyclic group (specifically, a 1H-tetrazolyl        group and the like), and

R⁵ is a hydrogen atom, a C₁₋₃ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group (specifically, a cyclopropyl group and the like),or a C₃₋₈ alkenyl group.

In other aspect, preferably, R⁴ is a hydrogen atom, a methyl group, anethyl group, a propyl group or a propenyl group, and R⁵ is a C₃₋₄ alkylgroup having 1 or 2 substituent(s) selected from the group of a carboxyland hydroxyl group.

In other aspect, preferably, R⁴ is a hydrogen atom, a methyl group, anethyl group, a propyl group or a propenyl group, and R⁵ is a C₁₋₆ alkylgroup having 1 or 2 substituent(s) selected from the group of a carboxylgroup, a hydroxyl group, an amino group and a carbamoyl group.

In other aspect, preferably, R⁴ and R⁵ are each independently a hydrogenatom or a C₁₋₈ alkyl group.

In other aspect, preferably, R⁴ and R⁵ together with the nitrogen atomto which they are bonded form a C₂₋₉ heterocycle substituted by ahalogen atom (specifically, a fluorine atom and the like), a carboxylgroup, a carboxyl C₁₋₃ alkyl group (specifically, a carboxylmethyl groupand the like) or a hydroxyl group.

As the C₁₋₈ alkyl group or the C₁₋₃ alkyl group for R⁴ and R⁵, a methylgroup, an ethyl group, a propyl group and the like can be mentioned.

As the carboxyl C₁₋₈ alkyl for R⁴ and R⁵, a linear or branched carboxylC₁₋₈ alkyl group such as a 1,2-dicarboxylethyl group, a carboxylmethylgroup, a 1-carboxyl-1-methylethyl group, a 1-carboxyl-2-methylpropylgroup, a 2-carboxylethyl group, a 1-carboxylethyl group, a1,3-dicarboxylpropyl group, a 1-carboxylpropyl group, a 1-carboxylbutylgroup, a 3-carboxylpropyl group, a 1-(carboxylmethyl)-2-methylpropylgroup, a 4-carboxylbutyl group, a1,1-bis(2-carboxylethyl)-3-carboxylpropyl group and a 5-carboxylpentylgroup; and a cyclic carboxyl C₃₋₈ alkyl group such as a1-carboxylcyclopropyl group, a 1-carboxylcyclobutyl group, a2-carboxylcyclohexyl group and a 3-carboxylcyclohexyl group can bementioned.

As the carboxyl C₁₋₃ alkyl for R⁴ and R⁵, a linear or branched carboxylC₁₋₃ alkyl group such as a 1,2-dicarboxylethyl group, a carboxylmethylgroup, a 1-carboxyl-1-methylethyl group, a 2-carboxylethyl group, a1-carboxylethyl group, a 1,3-dicarboxylpropyl group, a 1-carboxylpropylgroup and a 3-carboxylpropyl group; and a 1-carboxylcyclopropyl groupcan be mentioned.

As the C₃₋₈ alkenyl group for R⁴ and R⁵, an allyl group and the like canbe mentioned.

In one aspect, when the C₁₋₈ alkyl group, the carboxyl C₁₋₈ alkyl group,the C₃₋₈ alkenyl group, the C₁₋₃ alkyl group or the carboxyl C₁₋₃ alkylgroup for R⁴ or R⁵ has one or more substituents, unless otherwiseindicated, examples of the substituent include a nitro group, a halogenatom, a cyano group, a hydroxyl group, a sulfanyl group, an amino group,a guanidino group, a formyl group, a lower acyl group, a carboxyl group,a sulfo group, a phosphono group, a lower alkoxyl group, a loweralkylthio group, a lower alkylamino group, a lower acyloxy group, alower acylamino group, a lower alkoxycarbonyl group, a carbamoyl group,a lower alkylcarbamoyl group, a lower alkylsulfonylamino group, anarylsulfonylamino group optionally m having substituent(s), a cycloalkylgroup optionally having substituent(s), an aryl group optionally havingsubstituent(s), an aryloxy group optionally having substituent(s), anarylthio group optionally having substituent(s), an aralkyl groupoptionally having substituent(s), an aralkyloxy group is optionallyhaving substituent(s), an aralkylthio group optionally havingsubstituent(s), a heterocyclic group optionally having substituent(s), aheterocyclyloxy group optionally having substituent(s), aheterocyclylthio group optionally having substituent(s), an oxo groupand the like. A halogen atom, a hydroxyl group, a carboxyl group, asulfo group, a cyano group, a phosphono group, a lower alkoxycarbonylgroup, an aryl group optionally having substituent(s), a heterocyclicgroup optionally having substituent(s), an oxo group, and the like arepreferable, and a hydroxyl group, a carboxyl group, a sulfo group, alower alkoxycarbonyl group, and the like are particularly preferable. Acarboxyl group, a hydroxyl group, a carboxyl C₁₋₃ alkyl group, a C₃₋₈alkenyl group, a halogen atom, a carbamoyl group, a phenyl group, anamino group, a sulfo group, a cyano group, a C₃₋₈ cycloalkyl group, anda C₁₋₈ heterocyclic group containing 1-4 heteroatoms selected from thegroup consisting of O, N and S, and the like are also preferable. As forthe C₁₋₈ heterocyclic group containing 1-4 heteroatoms, a 1H-tetrazolylgroup, a 2,4-dioxo-1,3-thiazolidinyl group, and the like can bepreferably mentioned. The number of the substituents is preferably 1 to3, more preferably 1 or 2.

In other aspect, when the C₁₋₈ alkyl group, the carboxyl C₁₋₈ alkylgroup, the C₃₋₈ alkenyl group, the C₁₋₃ alkyl group or the carboxyl C₁₋₃alkyl group for R⁴ or R⁵ has one or more substituent, unless otherwiseindicated, examples of the substituent include a lower alkylcarbamoylgroup optionally having substituent(s), a hydroxyl group, a sulfo group,a cycloalkyl group, a carbamoyl group, an amino group, a cyano group, anaryl group optionally having substituent(s), a C₁₋₈ heterocyclic groupand the like. Preferable examples of the substituent include a C₁₋₃alkyl-carbamoyl group (specifically, an N-methylcarbamoyl group and thelike) optionally substituted by a carboxyl group, a hydroxyl group, asulfo group, a C₃₋₈ cycloalkyl group (specifically, a cyclopropyl group,a cyclohexyl group and the like), a carbamoyl group, an amino group, acyano group, an aryl group (specifically, a phenyl group and the like)optionally substituted by a carboxyl group or a hydroxyl group, a C₁₋₈heterocyclic group (specifically, a 1H-tetrazolyl group and the like)and the like. The number of the substituents is preferably 1 to 3, morepreferably 1 or 2.

As the C₂₋₉ heterocycle or the C₃₋₉ heterocycle (i.e., a cyclic aminogroup) formed by R⁴ and R⁵ bonded to each other, an aziridine ring, anazetidine ring, a pyrrolidine ring, a piperidine ring, atetrahydroisoquinoline ring and the like are preferable.

In one embodiment, when the C₂₋₉ heterocycle or the C₃₋₉ heterocycleformed by R⁴ and R⁵ bonded to each other has one or more substituents,unless otherwise indicated, examples of the substituent include a nitrogroup, a halogen atom, a cyano group, a hydroxyl group, a sulfanylgroup, an amino group, a guanidino group, a formyl group, a lower alkylgroup, a lower alkenyl group, a lower alkynyl group, a lower acyl group,a carboxyl group, a sulfo group, a phosphono group, a lower alkoxylgroup, a lower alkylthio group, a lower alkylamino group, a loweralkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group, alower alkylsulfonylamino group, a sulfamoyl group, an oxo group, and thelike. A carboxyl group, a hydroxyl group, a carboxyl C₁₋₃ alkyl group, aC₃₋₄₃ alkenyl group, a halogen atom, a carbamoyl group, a phenyl group,an amino group, a sulfo group, and a C₁₋₈ heterocyclic group containing1-4 heteroatoms selected from the group consisting of O, N and S, andthe like are preferable. A hydroxyl group, a carboxyl group, a sulfogroup, a phosphono group, a lower alkoxycarbonyl group, and the like arealso preferable. The number of the substituents is preferably 1 to 3,more preferably 1 or 2. As for the C₁₋₈ heterocyclic group containing1-4 heteroatoms, a 1H-tetrazolyl group, a 2,4-dioxo-1,3-thiazolidinylgroup, and the like can be preferably mentioned.

In other aspect, when the C₂₋₉ heterocycle or the C₃₋₉ heterocycleformed by R⁴ and R⁵ bonded to each other has one or more substituents,unless otherwise indicated, examples of the substituent include ahalogen atom, a hydroxyl group, a carboxyl group, a lower alkyl groupoptionally having substituent(s) and the like. Preferable examples ofthe substituent include a halogen atom (specifically, a fluorine atomand the like), a hydroxyl group, a carboxyl group, a carboxyl C₁₋₃ alkylgroup (specifically, a carboxylmethyl group and the like) and the like.The number of the substituents is preferably 1 to 3, more preferably 1or 2.

In the formula (II), R⁶ is a hydrogen atom, a C₁₋₈ alkyl group, acarboxyl C₁₋₈ alkyl group or a C₃₋₈ alkenyl group, wherein said C₁₋₈alkyl group, said carboxyl C₁₋₈ alkyl and said C₃₋₈ alkenyl group may besubstituted with one or more substituents.

In other aspect, in the formula (II), R⁶ is a hydrogen atom, a C₁₋₈alkyl group, a carboxyl C₁₋₈ alkyl group or a C₃₋₈ alkenyl group,wherein said C₁₋₈ alkyl group and said C₃₋₈ alkenyl group may besubstituted with one or more substituents.

Preferably, R⁶ is a hydrogen atom, a C₁₋₈ alkyl group or a C₃₋₈ alkenylgroup, wherein said C₁₋₈ alkyl group and said C₃₋₈ alkenyl group may besubstituted with one or more substituents.

More preferably, R⁶ is a hydrogen atom or a C₁₋₃ alkyl group, whereinsaid C₁₋₃ alkyl group may be substituted with one or more substituents.

In other aspect, preferably, R⁶ is a hydrogen atom, a C₁₋₃ alkyl groupoptionally substituted by a C₃₋₈ cycloalkyl group (specifically, acyclopropyl group and the like), or a C₃₋₈ alkenyl group.

In other aspect, preferably, R⁶ is a hydrogen atom or a C₁₋₈ alkylgroup.

As the C₁₋₃ alkyl group or the C₁₋₈ alkyl group for R⁶, a methyl group,a propyl group and the like can be mentioned. As the C₃₋₈ alkenyl groupfor R⁶, an allyl group and the like can be mentioned.

When the C₃₋₈ alkenyl group, the C₁₋₃ alkyl group, the C₁₋₈ alkyl groupor the carboxyl C₁₋₈ alkyl group for R⁶ has one or more substituents,unless otherwise indicated, examples of the substituent include acycloalkyl group. Preferable examples of the substituent include a C₃₋₈cycloalkyl group (specifically, a cyclopropyl group and the like).

In the formula (II), Ra and Rb are the same or different and each isindependently a hydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkylgroup, a carboxyl group, an aryl group, a C₃₋₆ heterocyclic groupcontaining 1 to 4 heteroatoms selected from the group of O, N and S, ora C₃₋₈ cycloalkyl group, or Ra and Rb together with the atom(s) to whichthey are bonded form a C₃₋₈ cycloalkane ring or a C₃₋₉ heterocyclecontaining 1-4 heteroatoms selected from the group of O, N and S,wherein said C₁₋₈ alkyl group, said aryl group, said C₃₋₈ cycloalkylgroup, said C₃₋₈ cycloalkane ring and said C₃₋₉ heterocycle may besubstituted with one or more substituents.

In other aspect, in the formula (II), Ra and Rb are the same ordifferent and each is independently a hydrogen atom, a C₁₋₈ alkyl group,a carboxyl C₁₋₈ alkyl group, a carboxyl group, an aryl group, a C₃₋₆heterocyclic group containing 1 to 4 heteroatoms selected from the groupof O, N and S, or a C₃₋₈ cycloalkyl group, or Ra and Rb together withthe atom(s) to which they are bonded form a C₃₋₈ cycloalkane ring or aC₃₋₉ heterocycle containing 1-4 heteroatoms selected from the group ofO, N and S, wherein said C₁₋₈ alkyl group, said carboxyl C₁₋₈ alkylgroup, said aryl group, said C₃₋₆ heterocyclic group, said cycloalkylgroup, said C₃₋₈ cycloalkane ring and said C₃₋₉ heterocycle may besubstituted with one or more substituents.

In the formula (II), when Ra and Rb do not form a ring, preferably, Raand Rb are the same or different from each other and each isindependently a hydrogen atom, a phenyl group, a C₁₋₈ alkyl group, acarboxyl group or a carboxyl C₁₋₈ alkyl group, wherein said phenylgroup, said C₁₋₈ alkyl group and said is carboxyl C₁₋₈ alkyl group maybe substituted with one or more substituents.

In the formula (II), when Ra and Rb do not form a ring, more preferably,Ra and Rb are the same or different from each other and each isindependently a hydrogen atom or a C₁₋₃ alkyl group, wherein said C₁₋₃alkyl group may be substituted with one or more substituents.

In the formula (II), when Ra and Rb form a ring, said ring ispreferably, a C₃₋₈ cycloalkane ring which may have one or moresubstituents, more preferably a cyclopropane ring, a cyclobutane ring ora cyclopentane ring, which may have one or more substituents.

In other aspect, preferably, Ra and Rb are the same or different andeach is independently a hydrogen atom or a C₁₋₈ alkyl group, or Ra andRb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, wherein said C₁₋₈ alkyl group and said C₃₋₈cycloalkane ring may substituted with a group selected from a carboxylgroup, a carbamoyl group, a hydroxyl group, a phenyl group and a C₃₋₈cycloalkyl group.

In other aspect, preferably, Ra and Rb are the same or different andeach is independently

(1) a hydrogen atom,

(2) a C₁₋₈ alkyl optionally group substituted by 1 to 3 substituentsselected from (a) an aryl group (specifically, a phenyl group), (b) ahydroxyl group, (c) a carbamoyl group, and (d) a C₁₋₈ heterocyclic groupcontaining 1 to 4 heteroatoms selected from O, N and S (specifically, a1H-tetrazolyl group),

(3) a carboxyl C₁₋₈ alkyl group,

(4) an aryl group optionally substituted by a hydroxyl group,

(5) a C₃₋₆ heterocyclic group containing 1 to 4 heteroatoms selectedfrom the group of O, N and S, or

(6) a C₃₋₈ cycloalkyl group, or

Ra and Rb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, or a C₃₋₉ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, each of which is optionallysubstituted by an oxo group.

As the C₁₋₈ alkyl group or the C₁₋₃ alkyl group for Ra and Rb, a methylgroup, an ethyl group, a propyl group, an isopropyl group, a sec-butylgroup and the like can be mentioned.

As the carboxyl C₁₋₈ alkyl group for Ra and Rb, a carboxylmethyl group,a 2-carboxylethyl group, and the like can be mentioned. As the arylgroup for Ra and Rb, a phenyl group and the like can be mentioned. Asthe C₃₋₆ heterocyclic group for Ra and Rb, a 1H-tetrazolyl group and thelike can be mentioned. As the C₃₋₈ cycloalkyl group for Ra and Rb, acyclohexyl group and the like can be mentioned.

When the C₁₋₈ alkyl group, the C₁₋₃ alkyl group, the carboxyl C₁₋₈ alkylgroup, the aryl group, the C₃₋₆ heterocyclic group or the C₃₋₈cycloalkyl group for Ra or Rb has one or more substituents, unlessotherwise indicated, examples of the substituent include a nitro group,a halogen atom, a cyano group, a hydroxyl group, a sulfanyl group, anamino group, a guanidino group, a formyl group, a lower acyl group, acarboxyl group, a sulfo group, a phosphono group, a lower alkoxyl group,a lower alkylthio group, a lower alkylamino group, a lower acyloxygroup, a lower acylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, an arylsulfonylamino group optionally havingsubstituent(s), a cycloalkyl group optionally having substituent(s), anaryl group optionally having substituent(s), an aryloxy group optionallyhaving substituent(s), an arylthio group optionally havingsubstituent(s), an aralkyl group optionally having substituent(s), anaralkyloxy group optionally having substituent(s), an aralkylthio groupoptionally having substituent(s), a heterocyclic group optionally havingsubstituent(s), a heterocyclyloxy group optionally havingsubstituent(s), a heterocyclylthio group optionally havingsubstituent(s), an oxo group, and the like. A carboxyl group, a hydroxylgroup, a phenyl group, an amino group, a lower alkylthio group, asulfanyl group, a carbamoyl group, a guanidino group, a C₃₋₈ cycloalkylgroup, a C₁₋₈ heterocyclic group containing 1 to 4 heteroatoms selectedfrom O, N and S, and the like are preferable, and a hydroxyl group, acarboxyl group, a sulfo group, a lower alkoxycarbonyl group, a1H-tetrazolyl group, and the like are particularly preferable.

In other aspect, when the C₁₋₈ alkyl group, the C₁₋₃ alkyl group, thecarboxyl C₁₋₈ alkyl group, the aryl group, the C₃₋₆ heterocyclic groupor the C₃₋₈ cycloalkyl group for Ra or Rb has one or more substituents,unless otherwise indicated, examples of the substituent include (a) anaryl group (specifically, a phenyl group), (b) a hydroxyl group, (c) acarbamoyl group, and (d) a C₁₋₈ heterocyclic group containing 1 to 4heteroatoms selected from O, N and S (specifically, a 1H-tetrazolylgroup) are particularly preferable.

In other aspect, when Ra or Rb has substituent(s), unless otherwiseindicated, said substituent is selected from a carboxyl group, ahydroxyl group, a phenyl group, an amino group, a methylthio group, asulfanyl group, a carbamoyl group, a guanidino group, a C₃₋₈ cycloalkylgroup, and a C₁₋₈ heterocyclic group containing 1-4 heteroatoms selectedfrom the group consisting of O, N and S.

As the C₃₋₈ cycloalkane ring formed by Ra and Rb bonded to each other, acyclopropane ring, a cyclobutane ring, a cyclopentane ring and the likecan be mentioned; a cyclopropane ring and a cyclobutane ring arepreferable.

As the C₃₋₉ heterocycle ring formed by Ra and Rb bonded to each other, atetrahydrofuran ring, a pyrrolidine ring and the like can be mentioned;a tetrahydrofuran ring is preferable.

When the C₃₋₈ cycloalkane ring, the C₃₋₉ heterocyclie, the cyclopropanering, the cyclobutane ring or the cyclopentane ring formed by Ra and Rbbonded to each other has one or more substituents, unless otherwiseindicated, examples of the substituent include a nitro group, a halogenatom, a cyano group, a hydroxyl group, a sulfanyl group, an amino group,a guanidino group, a formyl group, a lower alkyl group, a lower alkenylgroup, a lower alkynyl group, a lower acyl group, a carboxyl group, asulfo group, a phosphono group, a lower alkoxyl group, a lower alkylthiogroup, a lower alkylamino group, a lower alkoxycarbonyl group, acarbamoyl group, a lower alkylcarbamoyl group, a loweralkylsulfonylamino group, a sulfamoyl group, an oxo group, and the like.A carboxyl group, a hydroxyl group, an oxo group, a phenyl group, anamino group, a lower alkylthio group, a sulfanyl group, a carbamoylgroup, a guanidino group, a C₃₋₈ heterocyclic group containing 1 to 4heteroatoms selected from O, N and S, a C₃₋₈ cycloalkyl group, and thelike are preferable, and an oxo group is more preferable. The number ofthe substituents is preferably 1 to 3, more preferably 1 or 2,particularly preferably 1.

In the formula (II), Ring A is an arene (specifically, a benzene ringand the like), a C₃₋₆ heterocycle containing 1-4 heteroatoms selectedfrom the group of O, N and S (specifically, a pyridine ring and thelike), or a C₃₋₈ cycloalkane ring (specifically, a cyclohexane ring andthe like).

In other aspect, in the formula (II), Ring A is an arene (specifically,a benzene ring and the like), a C₃₋₆ heterocycle containing 1-4heteroatoms selected from the group of O, N and (specifically, apyridine ring, a 1,2-dihydropyridine ring, a tetrahydrofuran ring andthe like), a C₃₋₈ cycloalkane ring (specifically, a cyclohexane ring andthe like) or a C₃₋₈ cycloalkene ring (specifically, a cyclohexene ringand the like), wherein said C₃₋₆ heterocycle, said C₃₋₈ cycloalkane ringand said C₃₋₈ cycloalkene ring (preferably, said C₃₋₆ heterocycle) maybe further substituted with an oxo group, in addition to Ya and Yb.

In the formula (II), Ring A is, preferably, a benzene ring, a pyridinering, a 1,2-dihydropyridine ring, or a C₃₋₆ heterocycle containing 1-4oxygen atoms (specifically, a tetrahydrofuran ring and the like), morepreferably, a benzene ring, a pyridine ring or a C₃₋₆ heterocyclecontaining 1 to 4 oxygen atoms (specifically, a tetrahydrofuran ring andthe like), still more preferably, a benzene ring or a pyridine ring,most preferably, a benzene ring, wherein said 1,2-dihydropyridine ringand said C₃₋₆ heterocycle containing 1-4 oxygen atoms may be furthersubstituted with an oxo group, in addition to Ya and Yb.

In the formula (II), Ya is a hydrogen atom, a halogen atom, a carboxylgroup, a hydroxyl group, a carbonyl group (e.g., a C₁₋₃ alkoxy-carbonylgroup), a carboxyl C₁₋₃ alkyl group or a sulfo group.

In other aspect, in the formula (II), Ya is a hydrogen atom, a halogenatom, a carboxyl group, a hydroxyl group, a C₁₋₃ alkoxy-carbonyl group,a carboxyl C₁₋₃ alkyl group or a sulfo group.

In the formula (II), Ya is, preferably a carboxyl group, a carboxyl C₁₋₃alkyl group, a hydroxyl group, a sulfo group, a halogen atom or a C₁₋₃alkoxy-carbonyl group, more preferably, a carboxyl group, a carboxylC₁₋₃ alkyl group, a hydroxyl group or a halogen atom, even morepreferably, a carboxyl group or a carboxyl C₁₋₃ alkyl group.

As the halogen atom for Ya, a fluorine atom and the like can bementioned. As the carboxyl C₁₋₃ alkyl group for Ya, a carboxylmethylgroup and the like can be mentioned. As the C₁₋₃ alkoxy-carbonyl groupfor Ya, a methoxycarbonyl and the like can be mentioned.

In the formula (II), Yb is a hydrogen atom, a halogen atom, a carboxylgroup, a hydroxyl group, a carbonyl group (e.g., a C₁₋₃ alkoxy-carbonylgroup), a carboxyl C₁₋₃ alkyl group, a nitro group, a cyano group or aC₁₋₃ alkoxyl group.

In other aspect, in the formula (II), Yb is a hydrogen atom, a halogenatom, a carboxyl group, a hydroxyl group, a C₁₋₃ alkoxy-carbonyl group,a carboxyl C₁₋₃ alkyl group, a nitro group, a cyano group or a C₁₋₃alkoxyl group.

In the formula (II), Yb is, preferably a hydrogen atom, a C₁₋₃alkoxycarboxyl group, a hydroxyl group or a halogen atom, morepreferably, a carboxyl group or a hydroxyl group.

In other aspect, in the formula (II), Yb is preferably, a hydrogen atom,a halogen atom, a carboxyl group or a hydroxyl group.

In other aspect, in the formula (II), Yb is preferably, a hydrogen atom,a carboxyl group, a hydroxyl group, a C₁₋₃ alkoxy-carbonyl group or aC₁₋₃ alkoxyl group.

As the C₁₋₃ alkoxy-carbonyl group for Yb, a methoxycarbonyl group andthe like can be mentioned. As the C₁₋₃ alkoxyl group for Yb, a methoxygroup and the like can be mentioned.

In the formula (II), p is 0, 1, 2, 3 or 4, preferably, 0, 1, 2 or 3,more preferably, 0, 1 or 2.

In the formula (II), q is 0 or 1, preferably, 1.

In the formula (II), preferable combinations of p and q are when p=1 or2, and q=0, and when p=0 or 1, and q=1, further preferable combinationsare when p=1 or 2, and q=0, or when p=0 and q=1.

In the formula (I), R⁷ is a hydrogen atom, a halogen atom or a nitrogroup, preferably a hydrogen atom, a halogen atom such as a fluorineatom or a chlorine atom, more preferably, a halogen atom such as afluorine atom or a chlorine atom, still more preferably, a fluorineatom. The structure-activity relationship for the variation on thissubstituent is well-supported by the previous application by the presentinventors, WO2011/071048, which is incorporated herein by reference inits entirety.

In another preferable embodiment, in the formula (I), X is —OR³ or—NR⁸R⁹, preferably —OR³, more preferably —OH.

R⁸ is an optionally substituted C₁₋₈ alkyl group, an optionallysubstituted aryl group, an optionally substituted C₃₋₆ heterocyclicgroup, an optionally substituted C₃₋₈ cycloalkyl group, or an optionallysubstituted C₃₋₈ cycloalkenyl group, and

R⁹ is a hydrogen atom, an optionally substituted C₁₋₈ alkyl group or anoptionally substituted C₃₋₈ alkenyl group; or

R⁸ and R⁹ together with the nitrogen atom to which they are bonded forman optionally substituted C₂₋₉ heterocycle.

Preferably,

R⁸ is

-   -   (1) a C₁₋₈ alkyl group (e.g., a methyl group, an ethyl group, a        propyl group, an isopropyl group, a butyl group, an isobutyl        group, a pentyl group, a 1,2-dimethylbutyl group, a        1,1-diethylpropyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a carboxyl group,        -   (b) a hydroxyl group,        -   (c) an aryl group (e.g., a phenyl group) optionally            substituted by a carboxyl group or a hydroxyl group,        -   (d) a sulfo group,        -   (e) a C₃₋₈ cycloalkyl group (e.g., a cyclohexyl group),        -   (f) a carbamoyl group,        -   (g) an amino group,        -   (h) a cyano group,        -   (i) a C₁₋₈ heterocyclic group (e.g., a 1H-tetrazolyl group),            and        -   (j) a C₁₋₃ alkyl-carbamoyl group (e.g., an N-methylcarbamoyl            group) optionally substituted by a carboxyl group,    -   (2) an aryl group (e.g., a phenyl group) optionally substituted        by 1 to 3 substituents selected from        -   (a) a carboxyl group,        -   (b) a hydroxyl group,        -   (c) a C₁₋₃ alkyl group (e.g., a methyl group) optionally            substituted by a carboxyl group,        -   (d) a C₁₋₃ alkoxy-carbonyl group (e.g., a methoxycarbonyl            group), and        -   (e) a sulfo group,    -   (3) a C₃₋₈ heterocyclic group (e.g., a tetrahydrofuryl group, a        pyridyl group, a 1,2-dihydropyridyl group) optionally        substituted by 1 to 3 substituents selected from        -   (a) an oxo group,        -   (b) a C₁₋₃ alkoxyl group (e.g., a methoxy group), and        -   (c) a halogen atom (e.g., a fluorine atom),    -   (4) a C₁₋₈ cycloalkyl group (e.g., a cyclopropyl group, a        cyclobutyl group, a cyclohexyl group) optionally substituted by        a carboxyl group, or    -   (5) a C₃₋₈ cycloalkenyl group (e.g., a cyclohexenyl group)        optionally substituted by a carboxyl group, and

R⁹ is a hydrogen atom, a C₁₋₈ alkyl group (e.g., a methyl group, apropyl group) optionally substituted by a C₃₋₈ cycloalkyl group (e.g., acyclopropyl group), or a C₃₋₈ alkenyl group (e.g., an allyl group); or

R⁸ and R⁹ together with the nitrogen atom to which they are bonded forma C₂₋₉ heterocycle (e.g., an aziridine ring, an azetidine ring, apyrrolidine ring, a piperidine ring, a tetrahydroisoquinoline ring)optionally substituted by 1 to 3 substituents selected from

(1) a carboxyl group,

(2) a C₁₋₃ alkyl group (e.g., a methyl group) optionally substituted bya carboxyl group,

(3) a halogen atom (e.g., a fluorine atom), and

(4) a hydroxyl group.

In more preferable embodiment, X is preferably —OH or —NR^(8′)R^(9′),more preferably —OH, from the aspect of stability and few side effects.

R^(8′) is a substituted C₁₋₈ alkyl group, a substituted aryl group, asubstituted C₃₋₆ heterocyclic group, a substituted C₃₋₈ cycloalkylgroup, or a substituted C₃₋₈ cycloalkenyl group, each of which has onecarboxyl group, and

R^(9′) is a hydrogen atom, an optionally substituted C₁₋₈ alkyl groupwhich has no carboxyl group, or an optionally substituted C₃₋₈ alkenylgroup which has no carboxyl group; or

R^(8′) and R^(9′) together with the nitrogen atom to which they arebonded form a substituted C₂₋₉ heterocycle which has one carboxyl group.

Preferably,

R^(8′) is

-   -   (1) a C₁₋₈ alkyl group (e.g., a methyl group, an ethyl group, a        propyl group, an isopropyl group, a butyl group, an isobutyl        group, a pentyl group, a 1,2-dimethylbutyl group, a        1,1-diethylpropyl group) substituted by 1 to 3 substituents        selected from        -   (a) a carboxyl group,        -   (b) a hydroxyl group,        -   (c) an aryl group (e.g., a phenyl group) optionally            substituted by a carboxyl group or a hydroxyl group,        -   (d) a sulfo group,        -   (e) a C₃₋₈ cycloalkyl group (e.g., a cyclohexyl group),        -   (f) a carbamoyl group,        -   (g) an amino group,        -   (h) a cyano group,        -   (i) a C₁₋₈ heterocyclic group (e.g., a 1H-tetrazolyl group),            and        -   (j) a C₁₋₃ alkyl-carbamoyl group (e.g., an N-methylcarbamoyl            group) optionally substituted by a carboxyl group,

provided that said substituted C₁₋₈ alkyl group has one carboxyl group,

-   -   (2) an aryl group (e.g., a phenyl group) substituted by 1 to 3        substituents selected from        -   (a) a carboxyl group,        -   (b) a hydroxyl group,        -   (c) a C₁₋₃ alkyl group (e.g., a methyl group) optionally            substituted by a carboxyl group,        -   (d) a C₁₋₃ alkoxy-carbonyl group (e.g., a methoxycarbonyl            group), and        -   (e) a sulfo group,

provided that said substituted aryl group has one carboxyl group,

-   -   (3) a C₃₋₈ cycloalkyl group (e.g., a cyclopropyl group, a        cyclobutyl group, a cyclohexyl group) substituted by one        carboxyl group, or    -   (4) a C₃₋₈ cycloalkenyl group (e.g., a cyclohexenyl group)        substituted by one carboxyl group, and

R^(9′) is a hydrogen atom, a C₁₋₈ alkyl group (e.g., a methyl group, apropyl group) optionally substituted by a C₃₋₈ cycloalkyl group (e.g., acyclopropyl group), or a C₃₋₈ alkenyl group (e.g., an allyl group); or

R^(9′) and R^(9′) together with the nitrogen atom to which they arebonded form a C₂₋₉ heterocycle (e.g., an aziridine ring, an azetidinering, a pyrrolidine ring, a piperidine ring, a tetrahydroisoquinolinering) substituted by 1 to 3 substituents selected from

(1) a carboxyl group,

(2) a C₁₋₃ alkyl group (e.g., a methyl group) optionally substituted bya carboxyl group,

(3) a halogen atom (e.g., a fluorine atom), and

(4) a hydroxyl group,

provided that said substituted C₂₋₉ heterocycle formed by R^(8′) andR^(9′) has one carboxyl group.

More preferably,

R^(8′) is

-   -   (1) a C₁₋₈ alkyl group (e.g., a methyl group, an ethyl group, a        propyl group, an isopropyl group, a butyl group, an isobutyl        group, a pentyl group, a 1,2-dimethylbutyl group) substituted by        1 to 3 substituents selected from        -   (a) a carboxyl group,        -   (b) a hydroxyl group,        -   (c) an aryl group (e.g., a phenyl group) optionally            substituted by a carboxyl group or a hydroxyl group,        -   (d) a C₃₋₈ cycloalkyl group (e.g., a cyclohexyl group),        -   (e) a carbamoyl group,        -   (f) an amino group,        -   (g) a C₁₋₈ heterocyclic group (e.g., a 1H-tetrazolyl group),            and        -   (h) a C₁₋₃ alkyl-carbamoyl group (e.g., an N-methylcarbamoyl            group) optionally substituted by a carboxyl group,

provided that said substituted C₁₋₈ alkyl group has one carboxyl group,

-   -   (2) an aryl group (e.g., a phenyl group) substituted by 1 to 3        substituents selected from        -   (a) a carboxyl group,        -   (b) a hydroxyl group,        -   (c) a C₁₋₃ alkyl group (e.g., a methyl group) optionally            substituted by a carboxyl group, and        -   (d) a C₁₋₃ alkoxy-carbonyl group (e.g., a methoxycarbonyl            group),

provided that said substituted aryl group has one carboxyl group,

-   -   (3) a C₃₋₈ cycloalkyl group (e.g., a cyclopropyl group, a        cyclobutyl group, a cyclohexyl group) substituted by one        carboxyl group, or    -   (4) a C₃₋₈ cycloalkenyl group (e.g., a cyclohexenyl group)        substituted by one carboxyl group, and

R^(9′) is a hydrogen atom, a C₁₋₈ alkyl group (e.g., a methyl group, apropyl group) optionally substituted by a C₃₋₈ cycloalkyl group (e.g., acyclopropyl group), or a C₃₋₈ alkenyl group (e.g., an allyl group); or

R^(8′) and R^(9′) together with the nitrogen atom to which they arebonded form a C₂₋₉ heterocycle (e.g., an aziridine ring, an azetidinering, a pyrrolidine ring, a piperidine ring, a tetrahydroisoquinolinering) substituted by 1 to 3 substituents selected from

-   -   (1) a carboxyl group,    -   (2) a C₁₋₃ alkyl group (e.g., a methyl group) optionally        substituted by a carboxyl group, and    -   (3) a hydroxyl group,    -   provided that said substituted C₂₋₉ heterocycle formed by R^(8′)        and R^(9′) has one carboxyl group.

In the formula (I), when R¹ and R² are both methyl groups, then neitherof R⁴ nor R⁵ is an ethyl group substituted with two carboxyl groups, andwhen R¹ and R² are both methyl groups, then the group represented by theformula (II) is not a group represented by the formula:

In other aspect, in the formula (I), when R¹ and R² are both methylgroups, then X is not a group represented by the formula:

As preferable embodiments of the compound represented by the formula (I)or a pharmaceutically acceptable salt thereof, the following can also bementioned;

provided, however, that when R¹ and R² are both methyl groups, then X isnot a group represented by the formula:

in the formula (I).

Compound 1-A.

The compound represented by the formula (I) wherein,

R¹ and R² are both methyl groups,

X is —NR⁴R⁵, wherein

R⁴ is a hydrogen atom, a methyl group, an ethyl group, a propyl group ora propenyl group,

R⁵ is a C₃₋₄ alkyl group having 1 or 2 substituent(s) selected from thegroup of a carboxyl group and a hydroxyl group, and

R⁷ is a fluorine atom,

or a pharmaceutically acceptable salt thereof.

Compound 1-B.

The compound represented by the formula (I) wherein,

R¹ and R² are both ethyl groups,

X is —NR⁴R⁵, wherein

R⁴ is a hydrogen atom, a methyl group, an ethyl group, a propyl group ora propenyl group,

R⁵ is a C₁₋₆ alkyl group having 1 or 2 substituent(s) selected from thegroup of a carboxyl group, a hydroxyl group, an amino group and acarbamoyl group, and

R⁷ is a fluorine atom,

or a pharmaceutically acceptable salt thereof.

Compound 1-C.

The compound represented by the formula (I) wherein,

R¹ and R² are both methyl groups or an ethyl group,

X is the group represented by formula (II) wherein,

R⁶ is a hydrogen atom or a methyl group,

R⁷ is a fluorine atom,

p=0,

q=1,

Ring A is a phenyl group, a 3-pyridyl group or a 4-pyridyl group,

Ya is a hydrogen group, a carboxyl group, a hydroxyl group, a methoxygroup, a carboxylmethyl group, an oxo group or a halogen atom,

Yb is a hydrogen atom or a halogen atom, or a pharmaceuticallyacceptable salt thereof.

Compound 2-A.

The compound represented by the formula (I) wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³, —NR⁴R⁵ or the group represented by the formula (II) wherein,

R³ is a hydrogen atom or a C₁₋₄ alkyl group;

R⁴ is

-   -   (1) a carboxyl C₁₋₈ alkyl group optionally substituted by 1 to 3        substituents selected from (a) a hydroxyl group, (b) an aryl        group, (c) a C₃₋₈ cycloalkyl group, (d) a carbamoyl group, (e)        an amino group, (f) an aryl group optionally substituted by a        hydroxyl group, (g) a C₁₋₃ alkylcarbamoyl group optionally        substituted by a carboxyl group, and (h) a C₁₋₈ heterocyclic        group, or    -   (2) a C₁₋₈ alkyl group optionally substituted by 1 to 3        substituents selected from (a) a sulfo group, (b) a cyano        group, (c) a C₁₋₈ heterocyclic group, and (d) an aryl group        optionally substituted by a carboxyl group, and

R⁵ is a hydrogen atom, a C₁₋₃ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group; or

R⁴ and R⁵ together with the nitrogen atom to which they are bonded forma C₂₋₉ heterocycle substituted by 1 to 3 substituents selected from (1)a halogen atom, (2) a hydroxyl group, (3) a carboxyl group, and (4) acarboxyl C₁₋₃ alkyl group;

R⁶ is a hydrogen atom, a C₁₋₃ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group; and

Ra and Rb are the same or different and each is independently

-   -   (1) a hydrogen atom,    -   (2) a C₁₋₈ alkyl group optionally substituted by 1 to 3        substituents selected from (a) an aryl group, (b) a hydroxyl        group, (c) a carbamoyl group, and (d) a C₁₋₈ heterocyclic group        containing 1 to 4 heteroatoms selected from O, N and S,    -   (3) a carboxyl C₁₋₈ alkyl group,    -   (4) an aryl group optionally substituted by a hydroxyl group,    -   (5) a C₃₋₆ heterocyclic group containing 1 to 4 heteroatoms        selected from the group of O, N and S, or    -   (6) a C₃₋₈ cycloalkyl group, or

Ra and Rb together with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, or a C₃₋₉ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, each of which is optionallysubstituted by an oxo group;

Ring A is an arene, a C₃₋₆ heterocycle containing 1-4 heteroatomsselected from the group of O, N and S, a C₃₋₈ cycloalkane ring or a C₃₋₈cycloalkene ring, wherein said C₃₋₆ heterocycle, said C₃₋₈ cycloalkanering and said C₃₋₈ cycloalkene ring may be further substituted with anoxo group, in addition to Ya and Yb;

Ya is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a C₁₋₃ alkoxy-carbonyl group, a carboxyl C₁₋₃ alkyl group or asulfo group;

Yb is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxylgroup, a C₁₋₃ alkoxy-carbonyl group, a carboxyl C₁₋₃ alkyl group, anitro group, a cyano group or a C₁₋₃ alkoxyl group;

-   -   p is 0, 1, 2, 3 or 4;    -   q is 0 or 1; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group, or apharmaceutically acceptable salt thereof.

Compound 2-B.

The compound represented by the formula (I) wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³, wherein

R³ is a hydrogen atom or a C₁₋₄ alkyl group; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group, or apharmaceutically acceptable salt thereof.

Compound 2-C.

The compound represented by the formula (I) wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OH, and

R⁷ is a hydrogen atom, a halogen atom or a nitro group, or apharmaceutically acceptable salt thereof.

Compound 2-A′.

The compound represented by the formula (I) wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ m and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OR³ or —NR⁸R⁹; wherein

R³ is a hydrogen atom or a C₁₋₄ alkyl group;

R⁸ is

-   -   (1) a C₁₋₈ alkyl group optionally substituted by 1 to 3        substituents selected from (a) a carboxyl group, (b) a hydroxyl        group, (c) an aryl group optionally substituted by a carboxyl        group or a hydroxyl group, (d) a sulfo group, (e) a C₃₋₈        cycloalkyl group, (f) a carbamoyl group, (g) an amino group, (h)        a cyano group, (i) a C₁₋₈ heterocyclic group, and (j) a C₁₋₃        alkylcarbamoyl group optionally substituted by a carboxyl group,    -   (2) an aryl group optionally substituted by 1 to 3 substituents        selected from (a) a carboxyl group, (b) a hydroxyl group, (c) a        C₁₋₃ alkyl group optionally substituted by a carboxyl group, (d)        a C₁₋₃ alkoxy-carbonyl group, and (e) a sulfo group,    -   (3) a C₃₋₆ heterocyclic group optionally substituted by 1 to 3        substituents selected from (a) an oxo group, (b) a C₁₋₃ alkoxyl        group, and (c) a halogen atom,    -   (4) a C₃₋₈ cycloalkyl group optionally substituted by a carboxyl        group, or    -   (5) a C₃₋₈ cycloalkenyl group optionally substituted by a        carboxyl group, and

R⁹ is a hydrogen atom, a C₁₋₈ alkyl group optionally substituted by aC₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group; or

R⁸ and R⁹ together with the nitrogen atom to which they are bonded forma C₂₋₉ heterocycle optionally substituted by 1 to 3 substituentsselected from (1) a carboxyl group, (2) a C₁₋₃ alkyl group optionallysubstituted by a carboxyl group, (3) a halogen atom, and (4) a hydroxylgroup; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group, or apharmaceutically acceptable salt thereof.

Compound 2-B′.

The compound represented by the formula (I) wherein:

R¹ and R² are the same or different and each is independently a C₁₋₄alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring;

X is —OH or —NR^(9′)R^(9′), wherein

R^(8′) is

-   -   (1) a C₁₋₈ alkyl group substituted by 1 to 3 substituents        selected from (a) a carboxyl group, (b) a hydroxyl group, (c) an        aryl group optionally substituted by a carboxyl group or a        hydroxyl group, (d) a sulfo group, (e) a C₃₋₈ cycloalkyl        group, (f) a carbamoyl group, (g) an amino group, (h) a cyano        group, (i) a C₁₋₈ heterocyclic group, and (j) a C₁₋₃        alkylcarbamoyl group optionally substituted by a carboxyl group,        provided that said substituted C₁₋₈ alkyl group has one carboxyl        group,    -   (2) an aryl group substituted by 1 to 3 substituents selected        from (a) a carboxyl group, (b) a hydroxyl group, (c) a C₁₋₃        alkyl group optionally substituted by a carboxyl group, (d) a        C₁₋₃ alkoxy-carbonyl group, and (e) a sulfo group, provided that        said substituted aryl group has one carboxyl group,    -   (3) a C₃₋₈ cycloalkyl group substituted by one carboxyl group,        or    -   (4) a C₃₋₈ cycloalkenyl group substituted by one carboxyl group,        and

R^(9′) is a hydrogen atom, a C₁₋₈ alkyl group optionally substituted bya C₃₋₈ cycloalkyl group, or a C₃₋₈ alkenyl group; or

R^(8′) and R^(9′) together with the nitrogen atom to which they arebonded form a C₂₋₉ heterocycle substituted by 1 to 3 substituentsselected from (1) a carboxyl group, (2) a C₁₋₃ alkyl group optionallysubstituted by a carboxyl group, (3) a halogen atom, and (4) a hydroxylgroup, provided that said substituted C₂₋₉ heterocycle formed by R^(8′)and R^(9′) has one carboxyl group; and

R⁷ is a hydrogen atom, a halogen atom or a nitro group, or apharmaceutically acceptable salt thereof.

Compound 3-A.

A compound represented by any of the following formulas;

or a pharmaceutically acceptable salt thereof.

Compound 3-B.

A compound represented by any of the following formulas;

or a pharmaceutically acceptable salt thereof.

As the serine protease inhibitory activity, an activity m ofsimultaneously inhibiting trypsin and enteropeptidase is preferable.

When the compound of the present invention can form a salt, apharmaceutically acceptable salt is preferable. Examples of suchpharmaceutically acceptable salts for a compound having an acidic groupsuch as a carboxyl group and the like include an ammonium salt, saltswith alkali metals such as sodium, potassium, and the like, salts withalkaline earth metals such as calcium, magnesium, and the like, analuminum salt, a zinc salt, salts with an organic amines such astriethylamine, ethanolamine, morpholine, pyrrolidine, piperidine,piperazine, dicyclohexylamine, and the like, and salts with a basicamino acid such as arginine, lysine, and the like. Examples of suchpharmaceutically acceptable salts for a compound having a basic groupinclude salts with an inorganic acid such as hydrochloric acid, sulfuricacid, phosphoric acid, nitric acid, hydrobromic acid, and the like,salts with an organic carboxylic acid such as acetic acid, citric acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid,tannic acid, butyric acid, pamoic acid, enanthic acid, decanoic acid,salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid, andthe like, and salts with an organic sulfonic acid such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, andthe like.

The compound of the present invention also encompasses all opticalisomers, stereoisomers, tautomers, rotamers, and mixtures thereof atoptional ratios. These can be obtained each as a single productaccording to a synthesis method and separation method known per se. Forexample, an optical isomer can be obtained by using an optically activesynthesis intermediate or by optically resolving a racemate of asynthesis intermediate or final product by a conventional method.

The compound of the present invention also includes solvates of thecompound such as hydrates, alcohol adducts, and the like.

The compound of the present invention may be converted to a prodrug. Theprodrug of the present invention means a compound that is converted inthe body to produce the compound of the present invention. For example,when an active form contains a carboxyl group or a phosphoric acidgroup, an ester thereof, amide thereof, and the like can be mentioned.When an active form contains a carboxyl group, a group to be convertedto a carboxyl group by oxidative metabolism, such as a hydroxymethylgroup and the like can be mentioned. In addition, when the active formcontains an amino group, examples thereof include an amide thereof, acarbamate thereof, and the like. When the active form contains ahydroxyl group, examples thereof include esters thereof, carbonatesthereof, carbamates thereof, and the like. When the compound of thepresent invention is converted to a prodrug, it may be bonded to anamino acid or saccharide.

The present invention also encompasses a metabolite of the compound ofthe present invention. The metabolite of the compound of presentinvention means a compound resulting from the conversion of the compoundof the present invention by a metabolic enzyme and the like in the body.For example, a compound wherein a hydroxyl group is introduced on thebenzene ring of the compound of the present invention due to themetabolism, a compound wherein glucuronic acid, glucose, or an aminoacid is bonded to the carboxylic acid moiety of the compound of thepresent invention or a hydroxyl group is added by the metabolism, andthe like can be mentioned.

The compound of the present invention and a pharmaceutically acceptablesalt thereof have a superior blood glucose elevation suppressing actionfor mammals such as humans, bovines, horses, dogs, mice, rats, cats, andthe like, and can be used as a medicament, which is administered as itis or as a pharmaceutical composition containing the same mixed with apharmaceutically acceptable carrier according to a method known per se.While oral administration is generally preferable, parenteraladministration can also be employed (e.g., routes such as intravenous,subcutaneous, intramuscular, suppository, enema, ointment, patch,sublingual, eye drop, inhalation administrations, and the like). Whilethe dose used for the above-mentioned objects is determined according tothe desired treatment effect, administration method, duration oftreatment, age, body weight, and the like, a daily dose of 1 μg to 10 gfor oral administration and 0.01 μg to 1 g, preferably 0.1 μg to 1 g,for parenteral administration is used, which is generally administeredto an adult by an oral or parenteral route in one to several portionsper day. In addition, the content of the compound of the presentinvention in the above-mentioned pharmaceutical composition is about0.01 wt % to 100 wt % of the whole composition.

Examples of the pharmaceutically acceptable carrier for thepharmaceutical composition of the present invention include variousorganic or inorganic carrier substances conventionally used aspreparation materials. For example, an excipient, lubricant, binder,disintegrant, water-soluble polymer, and basic inorganic salt in a solidpreparation; a solvent, solubilizing agents, suspending agent,isotonicity agent, buffering agent, and soothing agent in a liquidpreparation, and the like can be mentioned. Where necessary, generaladditives such as a preservative, antioxidant, colorant, sweeteningagent, souring agent, effervescing agent, flavor, and the like can alsobe used.

The dosage form of such a pharmaceutical composition may be a tablet,powder, pill, granule, capsule, suppository, solution, sugar-coatedagent, depot, syrup, suspension, emulsion, troche, sublingual agent,adhesive preparation, oral disintegrant (tablet), inhalant, enema,ointment, patch, tape, or eye drop, and these can be produced usingconventional formulation auxiliaries and according to a conventionalmethod.

The pharmaceutical composition of the present invention can be producedaccording to a method conventionally used in the technical field ofpharmaceutical formulation, for example, the method described in theJapanese Pharmacopoeia, which is incorporated herein by reference in itsentirety, and the like. Specific production methods of the preparationare explained in detail in the following.

For example, when the compound of the present invention is prepared asan oral preparation, an excipient and, where necessary, a binder,disintegrant, lubricant, colorant, flavoring agent, and the like arefurther added, and the mixture is processed to give, for example, atablet, powder, pill, granule, capsule, suppository, solution,sugar-coated agent, depot, syrup, and the like according to aconventional method. Examples of the excipient include lactose,cornstarch, sucrose, glucose, sorbitol, crystalline cellulose, and thelike. Examples of the binder include polyvinyl alcohol, polyvinyl ether,ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin,shellac, hydroxypropylcellulose, hydroxypropylstarch,polyvinylpyrrolidone, and the like. Examples of the disintegrant includestarch, agar, gelatin powder, crystalline cellulose, calcium carbonate,sodium hydrogen carbonate, calcium citrate, dextran, pectin, and thelike. Examples of the lubricant include magnesium stearate, talc,polyethylene glycol, silica, hydrogenated vegetable oil, and the like.As the colorant, one acceptable to add to a pharmaceutical product isused, and as the flavoring agent, cocoa powder, menthol, aromatic acid,peppermint oil, borneol, powdered cinnamon bark, and the like are used.Where necessary, these tablets and granules are applied with a coatingas appropriate such as a sugar coating, gelatin coating, and the like.

When an injection is to be prepared, a pH adjuster, buffering agent,stabilizer, preservative, and the like are added where necessary, andthe mixture is processed to give subcutaneous, intramuscular, orintravenous injection according to a conventional method.

While the compound of the present invention can be used as an agent forthe treatment or prophylaxis of diabetes as mentioned above, it can alsobe used in combination with other therapeutic agents for diabetes andagents for the treatment or prophylaxis of diabetic complications, whichare used generally. Examples of the therapeutic agents for diabetes andagents for the treatment or prophylaxis of diabetic complications, whichare used generally, include combinations and mixtures of one or morekinds of an insulin preparation, insulin derivative, insulin-like agent,insulin secretagogue, insulin sensitizer, biguanide, gluconeogenesisinhibitor, glucose absorption inhibitor, renal glucose reabsorptioninhibitor, β3 adrenoceptor agonist, glucagon-like peptide-1 (7-37),glucagon-like peptide-1 (7-37) analogs, glucagon-like peptide-1 receptoragonist, dipeptidyl peptidase IV inhibitor, aldose reductase inhibitor,inhibitor of advanced glycation end product formation, glycogen synthasekinase-3 inhibitor, glycogen phosphorylase inhibitor, antihyperlipidemicdrug, anorectic agent, lipase inhibitor, antihypertensive agent,peripheral circulation improving agent, antioxidant, a therapeutic drugfor diabetic neuropathy, and the like.

A medicament to be used in combination with the compound of the presentinvention may be mixed to give a single agent or each may be formulatedinto separate preparations, or prepared into a combination preparation(set, kit, or pack) obtained by packaging each of the separatelyformulated preparations in one container.

The administration form of combined use is not particularly limited and,for example, (1) administration as a single preparation, (2)simultaneous administration of separate preparations by the sameadministration route, (3) administration of separate preparations in astaggered manner by the same administration route, (4) simultaneousadministration of separate preparations by different administrationroutes, (5) administration of separate preparations in a staggeredmanner by different administration routes, and the like can bementioned.

In addition, the compound of the present invention is also useful evenwhen contained in food.

A food composition containing the compound of the present invention isuseful as a food for the treatment or prophylaxis of diabetes.

The “food” of the present invention means general foods, which includefoods for specified health uses and foods with nutrient function claimsdefined by Food with Health Claims of Consumer Affairs Agency,Government of Japan, in addition to general foods including so-calledhealth food, and further encompasses dietary supplements.

The form of the food composition of the present invention is notparticularly limited, and the composition may take any form as long asit can be orally ingested.

Examples thereof include a powder, granule, tablet, hard capsules, softcapsule, liquid (drinks, jelly drinks, and the like), candy, chocolate,and the like, all of which can be produced according to a method knownper se in the technical field.

The content of the compound of the present invention in the foodcomposition is appropriately determined to afford an appropriate dosewithin the indicated range.

The food composition of the present invention can use other foodadditives as necessary. Examples of such food additives include thosegenerally used as components of health foods such as a fruit juice,dextrin, cyclic oligosaccharide, saccharides (monosaccharides such asfructose, glucose, and the like, and polysaccharides), acidulant,flavor, powdered green tea, and the like, which are used for controllingand improving taste, emulsifier, collagen, whole milk powder,polysaccharide thickener, agar, and the like, which are used forimproving texture, and further, vitamins, eggshell calcium, calciumpantothenate, the other minerals, royal jelly, propolis, honey, dietaryfiber, Agaricus, chitin, chitosan, flavonoids, carotenoids, lutein,traditional Japanese herbal medicine, chondroitin, various amino acids,and the like.

A production method of the representative compound of theheteroarylcarboxylic acid ester derivatives represented by the formula(I), which is the compound of the present invention, is shown below.

Heteroarylcarboxylic acid ester derivative (H) represented by theformula (I) wherein X is —OR³, and R³ is as previously defined, can beproduced as follows.

wherein E₁ is a protecting group such as a methyl group, an ethyl group,a tert-butyl group, a benzyl group, and the like, E₂ is similar to R³,and R¹, R² and R⁷ are as previously defined.

Alkenylene derivative (C) can be synthesized by reacting aldehyde (A)with Wittig reagent (B) in, for example, a solvent that does notadversely influence the reaction, such as tetrahydrofuran,N,N-dimethylformamide and the like, in the presence of, for example, abase such as sodium hydride and the like. Alkenylene derivative (C) canbe converted to alkylene derivative (D) by hydrogenation in the presenceof a catalyst, for example, 10% palladium/carbon, palladiumhydroxide/carbon, and the like under a hydrogen atmosphere in a solventthat does not adversely influence the reaction, such as ethyl acetate,methanol, tetrahydrofuran, dichloromethane, chloroform and the like.

After converting alkylene derivative (D) into the enolate with a basesuch as lithium bis(trimethylsilyl)azanide, lithium diisopropylamide,and the like in a solvent, for example tetrahydrofuran,N,N-dimethylformamide, and like, at low temperature, it can be reactedwith R2-Z (wherein Z is a leaving group such as an iodine atom, abromine atom and the like) to can lead to dialkyl derivative (E).

Carboxylic acid derivative (F) can be obtained by deprotecting dialkylderivative (E) by, for example, hydrolysis with a base such as sodiumhydroxide and the like, hydrolysis with an acid such as hydrochloricacid, trifluoroacetic acid and the like or treating with, for example,10% palladium/carbon and the like under a hydrogen atmosphere.

Heteroarylcarboxylic acid ester derivative (H) can be produced byesterifying carboxylic acid derivative (F) with amidinophenol derivative(G).

The esterification reaction can be performed by a known method which is,for example, (1) a method using an acid halide, (2) a method using acondensation agent and the like.

(1) The method using an acid halide is performed, for example, byreacting an acid chloride obtained by reaction with thionyl chloride,oxalyl chloride, and the like in a solvent that does not adverselyinfluence the reaction, such as dichloromethane, N-methylpyrrolidone,and the like, or without solvent in the presence or absence of, forexample, a catalyst such as N,N-dimethylformamide and the like, with thealcohol in a solvent that does not adversely influence the reaction suchas dichloromethane, tetrahydrofuran, and the like in the presence of abase such as pyridine and triethylamine.

(2) The method using a condensation agent is performed, for example, byreacting the carboxylic acid with the alcohol in, for example, a solventthat does not adversely influence the reaction such as tetrahydrofuran,N,N-dimethylformamide, dichloromethane, 1,2-dichloloethane, pyridine,and the like in, for example, the presence or absence of a base such aspyridine, triethylamine, and the like, by using a condensation agentsuch as 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSC),1,3-dicyclohexylcarbodiimide, and the like.

wherein, each symbol is as previously defined, provided, however, that Xis other than —OR³.

Heteroarylcarboxylic acid ester derivative (H) can be converted tocarboxylic acid derivative (i) in the same manner as in theafore-mentioned deprotection reaction.

Heteroarylcarboxylic acid ester derivative (I) can be produced byamidating carboxylic acid derivative (i) with amine (J) or (K). H—NR⁸R⁹or H—NR^(8′)R^(9′) wherein each symbol is as previously defined, may beinstead of amine (J) or (K). The amidation reaction of the carboxylicacid derivative is performed using the corresponding amine instead of analcohol and in the same manner as in the aforementioned esterificationreaction.

Dialkyl derivative (E) can be also synthesized by reacting alpha-dialkylcarboxylic acid (L) with alkyl halide (M) (wherein Z is a leaving groupsuch as a chlorine atom, a bromine atom and the like).

wherein, each symbol is as previously defined.

After converting alpha-dialkyl carboxyric acid (L) into the enolate witha base such as lithium bis(trimethylsilyl)azanide, lithiumdiisopropylamide, and the like in a solvent, for exampletetrahydrofuran, N,N-dimethylformamide, and like, at low temperature, itcan be reacted with alkyl halide (M) and to lead to dialkyl derivative(E′).

Dialkyl derivative (E′) can be converted to heteroarylcarboxylic acidester derivative (I) in the same manner as in the afore-mentionedprotection, deprotection, esterification, and amidation.

Amines (J) or (K) can be obtained according to the following Examples orany know methods.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Synthesis ofN-[1-{5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-ylmethyl}cyclobutylcarbonyl]-L-asparticacid trifluoroacetic acid salt (compound 1) Step 1. Synthesis of3-fluoro-4-hydroxylbenzamidine hydrochloride

To 3-fluoro-4-hydroxybenzonitrile (7.56 g, 55.2 mmol) were added ethanol(20 mL) and 4N-hydrogen chloride in 1,4-dioxane (100 mL), and themixture was stirred at room temperature. After 5 days, the mixture wasconcentrated and dried with a vacuum pump. Then, the mixture wasdissolved in ethanol (100 mL), ammonium carbonate (11.0 g, 115 mmol) wasadded, and the mixture was stirred at room temperature. After 12 hours,the solvent was evaporated, and the residue was dissolved in water (100mL). The mixture was lyophilized to give the title compound (11.2 g,quantitative).

1H-NMR (300 MHz, DMSO-d6) δ 11.28 (1H, br s), 9.19 (2H, br s), 9.02 (2H,br s), 7.75 (1H, dd, J=2.4, 12.0 Hz), 7.59 (1H, m), 7.18 (1H, dd, J=8.4,8.7 Hz).

MS(ESI) m/z 155(M+H)+

Step 2. Synthesis of 5-formyl-2-thiophencarboxylic acid tert-butyl ester

To a solution of 5-formyl-2-thiophencarboxylic acid (25 g, 0.16 mol) intert-butyl alcohol (200 mL) and dichloromethane (100 mL) was addeddi-tert-butyl dicarbonate (41 g, 0.19 mol), N,N-dimethylaminopyridine(2.0 g, 0.016 mol), and pyridine (5 mL), and the mixture was stirred atroom temperature for 24 hours. The reaction mixture was concentratedunder reduced pressure. The residue was added to ethyl acetate and0.5N-hydrochloric acid solution, the organic layer was separated, andthe aqueous layer was extracted two times with ethyl acetate. Theorganic layers were combined, washed with 0.5 N sodium hydroxidesolution and brine, and dried over anhydrous magnesium sulfate. Thesolvent of the filtrate after filtration was evaporated under reducedpressure to give the title compound (32.1 g, 0.15 mol, 94%).

¹H-NMR (400 MHz, CDCl₃) δ 9.95 (1H, s), 7.75 (1H, d, J=4.0 Hz), 7.70(1H, d, J=4.0 Hz), 1.59 (9H, s).

Step 3. Synthesis of 5-chloromethyl-2-thiophencarboxylic acid tert-butylester

To a solution of 5-formyl-2-thiophencarboxylic acid tert-butyl ester (5g, 23.6 mmol) in tetrahydrofuran (50 mL) and methanol (5 mL), was addedsodium borohydride (0.50 g, 13.0 mmol) at 0° C., and the mixture wasstirred for 2 hours at room temperature. The reaction mixture waspartitioned between ethyl acetate and 0.5N-hydrochloric acid solution.The aqueous layer was extracted with ethyl acetate, and the combinedorganic layers were washed with brine and dried over anhydrous magnesiumsulfate. The solvent was removed under reduced pressure, and theobtained residue was dissolved in dichloromethane (100 mL),methanesulfonyl chloride (1.9 ml, 24 mmol) and diisopropylethylamine(5.7 ml, 33 mmol) were added at 0° C., and the mixture was stirred atroom temperature overnight. The solvent was evaporated under reducedpressure, 0.5N-hydrochloric acid solution was added to the residue, andthe mixture was extracted with ethyl acetate. The extract was washedwith brine, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography to give the title compound (5.3 g, 23 mmol).

¹H NMR (400 MHz, CDCl₃) δ 7.56 (1H, d, J=3.8 Hz), 7.03 (1H, d, J=3.8Hz), 4.75 (2H, s), 1.57 (9H, s).

Step 4. Synthesis of1-{5-(tert-butoxycarbonyl)thiophen-2-ylmethyl}cyclobutylcarboxylic acid

To a solution of diisopropylamine (905 μL, 6.44 mmol) in tetrahydrofuran(0.5 mL), was added n-butyllithium (3.9 mL, 1.65 M in hexane) at −78° C.After stirring at 0° C. for 25 minutes, a mixture was cooled to −78° C.Cyclobutylcarboxylic acid (372 μL, 3.58 mmol) was added to the reactionmixture, and stirred at room temperature for 15 minutes. After cooled to−78° C., 5-chloromethyl-2-thiophencarboxylic acid tert-butyl esterobtained in step 3 (333 mg, 1.43 mmol) in tetrahydrofuran (0.5 mL) wasadded to the reaction mixture. After stirred at room temperature for 2hours, the reaction mixture was partitioned between ethyl acetate and1N-hydrochloric acid solution. The aqueous layer was extracted withethyl acetate, and the combined organic layers were washed with brineand dried over anhydrous magnesium sulfate. The solvent was removedunder reduced pressure, and the obtained residue was purified by highperformance liquid chromatography (water-acetonitrile, each containing0.1% trifluoroacetic acid) to give the title compound (60 mg, 0.201mmol, 14%).

1H-NMR (400 MHz, CDCl₃) δ 7.53 (1H, d, J=3.7 Hz), 6.79 (1H, d, J=3.7Hz), 3.30 (2H, s), 2.63-2.47 (2H, m), 2.18-2.05 (2H, m), 2.05-1.88 (2H,m), 1.53 (9H, s).

MS(ESI) m/z 297 (M+H)+

Step 5. Synthesis ofN-{1-(5-carboxylthiophen-2-ylmethyl)cyclobutylcarbonyl}-L-aspartic aciddimethyl ester

3-{5-(tert-butylcarboxyl)thiophen-2-yl}-2-cyclobutylpropanoic acid (50mg, 0.169 mmol) was solved in sulfonyl chloride (0.5 mL), and stirred at60° C. for 30 minutes. After the solvent was removed under reducedpressure, to a solution of the product obtained in step 4 indichloromethane (0.3 mL) was added L-aspartic acid dimethyl ester (50mg, 0.253 mmol), and pyridine (0.3 mL). After the reaction mixture wasstirred at room temperature for 1 hour, WSC hydrochloride (60 mg,0.338=1) was added and stirred at room temperature for 3 hours. Afterthe solvent was removed under reduced pressure, the residue was resolvedin trifluoroacetic acid (0.5 mL). After the solution was stirred at roomtemperature for 1 hour, the reaction mixture was concentrated underreduced pressure. The obtained residue was purified by high performanceliquid chromatography (water-acetonitrile, each containing 0.1%trifluoroacetic acid) to give the title compound (32 mg, 0.093 mmol,55%).

1H-NMR (400 MHz, DMSO-d6) δ 8.18 (1H, d, J=7.9 Hz), 7.52 (1H, d, J=3.7Hz), 6.85 (1H, d, J=3.7 Hz), 4.72-4.53 (1H, m), 3.61 (3H, s), 3.60 (3H,s), 3.28 (2H, s), 2.84 (1H, dd, J=16.2, 6.2 Hz), 2.66 (1H, dd, J=16.2,7.9 Hz), 2.39-2.20 (2H, m), 2.01-1.78 (3H, m), 1.77-1.63 (1H, m).

MS(ESI) m/z 384 (M+H)+

Step 6. Synthesis ofN-[1-{5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-ylmethyl}cyclobutylcarbonyl]-L-asparticacid trifluoroacetic acid salt (compound 1)

To a solution ofN-{3-(5-carboxylthiophen-2-yl)-2-cyclobutylpropanoyl}-L-aspartic aciddimethyl ester (30 mg, 0.087 mmol) in pyridine (1.0 mL), was added3-fluoro-4-hydroxylbenzamidine hydrochloride (25 mg, 0.131 mmol) and WSChydrochloride (34 mg, 0.175 mmol), and the mixture was stirred at roomtemperature overnight. After the solvent was removed under reducedpressure, the obtained residue was dissolved in 4N-hydrogen chloride in1,4-dioxane (0.6 mL) and water (0.2 mL). After the reaction mixture wasstirred at 60° C. for 9 hours, the reaction mixture was concentratedunder reduced pressure. The obtained residue was purified by highperformance liquid chromatography (water-acetonitrile, each containing0.1% trifluoroacetic acid) to give the title compound (18 mg, 0.030mmol, 34%).

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.09 (2H, br s), 8.07 (1H,d, J=8.0 Hz), 7.99-7.83 (2H, m), 7.92-7.82 (1H, m), 7.79-7.69 (2H, m),7.06 (1H, d, J=3.9 Hz), 4.56 (1H, dd, J=13.9, 7.6 Hz), 3.48 (2H, s),2.74 (1H, dd, J=16.4, 6.0 Hz), 2.64-2.49 (1H, m), 2.40-2.25 (2H, m),2.05-1.83 (3H, m), 1.80-1.69 (1H, m).

MS(ESI) m/z 492 (M+H)+

Example 2 Synthesis ofN-{1-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-ylmethyl]cyclopentylcarbonyl}-L-asparticacid trifluoroacetic acid salt (compound 2)

The compound 2 was synthesized by an operation in the same manner as inthe above-mentioned Example 1.

1H-NMR (400 MHz, DMSO-d6) δ 9.36 (2H, br s), 9.08 (2H, br s), 7.97 (1H,d, J=7.9 Hz), 7.89-7.80 (2H, m), 7.72-7.63 (2H, m), 7.00 (1H, d, J=3.9Hz), 4.49 (2H, dt, J=12.9, 6.4 Hz), 3.17 (2H, s), 2.69 (1H, dd, J=16.4,6.0 Hz), 2.57-2.45 (2H, m), 2.02-1.81 (2H, m), 1.63-1.37 (6H, m).

MS(ESI) m/z 506 (M+H)+

Example 3 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}-L-valinehydrochloride (compound 9) Step 1. Synthesis of2-(diethylphosphono)propanoic acid methyl ester

Methyl 2-bromopropionate (100 g, 0.60 mol) and triethylphosphite (109 g,0.66 mol) were mixed, and the mixture was stirred at 110° C. for 2 days.The reaction mixture was dried under reduced pressure to give the titlecompound.

Step 2. Synthesis of5-[(1E)-2-(methoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylic acidtert-butyl ester

2-(Diethylphosphono)propanoic acid methyl ester (23.0 g, 0.103 mol) wasdissolved in tetrahydrofuran (150 mL), 60% sodium hydride (2.4 g, 0.06mol) was added at 0° C., and the mixture was stirred for 30 minutes. Tothe reaction mixture was added a solution of5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example1, step 2 (11.0 g, 0.052 mol) in tetrahydrofuran (10 mL), and themixture was stirred at room temperature overnight. The solvent wasevaporated, and the residue was partitioned between ethyl acetate and1N-hydrochloric acid solution, and washed successively with water andbrine. After drying over anhydrous magnesium sulfate, the residue waspurified by silica gel column chromatography to give the title compound(13.1 g, 0.047 mol, 90%).

¹H-NMR (400 MHz, CDCl₃) δ 7.89 (1H, s), 7.68 (1H, d, J=4.0 Hz), 7.19(1H, d, J=4.0 Hz), 3.82 (3H, s), 2.24 (3H, s), 1.59 (9H, s).

Step 3. Synthesis of 5-(2-methoxycarbonylpropyl)thiophene-2-carboxylicacid tert-butyl ester

5-[(1E)-2-(methoxycarbonyl)-prop-1-en-1-yl]thiophene-2-carboxylic acidtert-butyl ester (13.77 g, 0.049 mol) was dissolved in ethyl acetate (60mL), methanol (20 mL), and chloroform (10 mL), palladium hydroxide (2.8g) was added, and the mixture was stirred at room temperature overnightunder a hydrogen atmosphere. After completion of the reaction, palladiumhydroxide was removed by celite filtration, and the solvent wasevaporated under reduced pressure to give the title compound (13.14 g,0.046 mol, 94%).

¹H-NMR (400 MHz, CDCl₃) δ 7.53 (1H, d, J=4.0 Hz), 6.77 (1H, d, J=4.0Hz), 3.67 (3H, s), 3.18 (1H, dd, J=14.4, 7.2 Hz), 2.91 (1H, dd, J=14.4,7.2 Hz), 2.77 (1H, m), 1.56 (9H, s), 1.21 (3H, d, J=7.2 Hz).

Step 4. Synthesis of5-(2-methyl-2-methoxycarbonylpropyl)thiophene-2-carboxylic acidtert-butyl ester

5-(2-Methoxycarbonylpropyl)thiophene-2-carboxylic acid tert-butyl ester(13.14 g, 46.3 mmol) was dissolved in tetrahydrofuran (250 mL), 1.09 Mlithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (65 mL, 70.9mmol) was added dropwise at −78° C., and the mixture was stirred for 2hours. To the reaction mixture was added methyl iodide (11.7 g, 82.4mmol) at −78° C., and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure.The residue was added to ethyl acetate and 0.5N-hydrochloric acidsolution, the organic layer was separated, and the aqueous layer wasextracted two times with ethyl acetate. The organic layers werecombined, washed with sodium thiosulfate solution and brine, and driedover anhydrous magnesium sulfate. The solvent of the filtrate afterfiltration was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound (12.36 g, 41.4 mmol, 89%).

¹H-NMR (400 MHz, CDCl₃) δ 7.53 (1H, d, J=3.6 Hz), 6.73 (1H, d, J=3.6Hz), 3.71 (3H, s), 3.05 (2H, s), 1.56 (9H, s), 1.23 (6H, s).

Step 5. Synthesis of3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropanoicacid trifluoroacetic acid salt

To 5-(2-Methyl-2-methoxycarbonylpropyl)thiophene-2-carboxylic acidtert-butyl ester (5.0 g, 16.8 mmol) was added trifluoroacetic acid (20mL), and the mixture was stirred at room temperature for 30 minutes. Thesolvent was evaporated, and the residue was dissolved in pyridine (30mL), 3-fluoro-4-hydroxybenzamidine hydrochloride (3.2 g, 16.8 mmol) andWSC hydrochloride (3.8 g, 19.8 mmol) were added, and the mixture wasstirred at 50° C. for 5 hours. The reaction mixture was concentratedunder reduced pressure, 4N-hydrochloric acid solution (10 mL) and4N-Hydrogen chloride in 1,4-Dioxane (10 mL) were added to the obtainedresidue, and the mixture was stirred at 80° C. for 2 hours. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound (2.8 g, 5.86 mmol, 35%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.96 (1H,d, J=4.0 Hz), 7.93 (1H, d, J=8.1 Hz), 7.80-7.70 (2H, m), 7.09 (1H, d,J=4.0 Hz), 3.14 (2H, s), 1.16 (6H, s).

MS(ESI) m/z 365(M+H)+

Step 6. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}-L-valinehydrochloride (compound 9)

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropanoicacid trifluoroacetic acid salt obtained in step 5 (53 mg, 0.10 mmol) wasdissolved in thionyl chloride (3 mL), and the mixture was stirred atroom temperature for 3 hours. Thionyl chloride was evaporated underreduced pressure to give the acid chloride. The obtained acid chloridewas dissolved in dichloromethane (3 mL), L-valine tert-butyl esterhydrochloride (25 mg, 0.12 mmol) and pyridine (0.1 mL) were addedthereto, and the mixture was stirred at room temperature overnight.After evaporation of the solvent, trifluoroacetic acid (2 mL) was added,and the mixture was stirred at room temperature 1 hour. The mixture wasconcentrated under reduced pressure. The obtained residue was purifiedby high performance liquid chromatography (water-acetonitrile, eachcontaining 0.1% trifluoroacetic acid) to give the trifluoroacetic acidsalt of the title compound.

To the obtained trifluoroacetic acid salt was added 0.05N-hydrochloricacid solution (10 mL), and the mixture was lyophilized to give the titlecompound (40 mg, 0.80 mmol, 80%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 8.00-7.89(2H, m), 7.80-7.70 (2H, m), 7.57 (1H, d, J=7.2 Hz), 7.08 (1H, s), 4.13(1H, m), 3.21 (1H, d, J=16.0 Hz), 3.15 (1H, d, J=16.0 Hz), 2.15-2.05(1H, m), 1.76-1.50 (4H, m), 0.90 (3H, d, J=6.8 Hz), 0.86-0.75 (6H, m).

MS(ESI) m/z 464 (M+H)+

Example 4 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}-N-propylglycinehydrochloride (compound 10) Step 1. Synthesis of N-allylglycine benzylester hydrochloride

To a solution of allylamine hydrochloride (5.0 g, 53.4 mmol) intetrahydrofuran (100 mL) was added diisopropylethylamine (10 mL) andbromoacetic acid benzyl ester (3.06 g, 13.3 mmol) at 0° C. and themixture was stirred at room temperature overnight. The reaction mixturewas concentrated under reduced pressure. The residue was added ethylacetate and 1 N-hydrochloric acid solution, the organic layer wasseparated, and the aqueous layer was extracted two times with ethylacetate. The organic layers were combined, washed with sodiumthiosulfate solution and brine, and dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography, and to the obtainedoil was added 4N-Hydrogen chloride in 1,4-Dioxane (3.5 mL). The mixturewas concentrated under reduced pressure and lyophilized to give thetitle compound (2.12 g, 8.79 mmol, 66%).

¹H-NMR (400 MHz, CDCl₃) δ 7.40-7.35 (5H, m), 6.12-6.02 (1H, m),5.49-5.43 (2H, m), 5.22 (2H, s), 3.82 (2H, s), 3.78 (2H, d, J=7.2 Hz).

MS(ESI) m/z 206(M+H)+

Step 2. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}-N-allylglycinebenzyl ester trifluoroacetic acid salt

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropanoicacid trifluoroacetic acid salt (100 mg, 0.20 mmol) obtained in Example3, step 5 was dissolved in thionyl chloride (3 mL), and the mixture wasstirred at 60° C. for 20 minutes. Thionyl chloride was evaporated underreduced pressure to give the acid chloride. The obtained acid chloridewas dissolved in dichloromethane (5 mL), N-allylglycine benzyl esterhydrochloride obtained in step 1 (51 mg, 0.21 mmol) and pyridine (0.1mL) were added thereto, and the mixture was stirred at room temperatureovernight. The mixture was concentrated under reduced pressure. Theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe title compound. (37 mg, 0.056 mmol, 28%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.40 (2H, br s), 9.05 (2H, br s), 7.90 (2H,m), 7.72 (2H, m), 7.38-7.28 (5H, m), 7.11 (1H, d, J=4.0 Hz), 5.86-5.73(1H, m), 5.25-5.15 (2H, m), 5.12 (2H, s), 4.28-4.18 (2H, m), 4.01-4.91(2H, m), 3.19 (2H, s), 1.23 (6H, s).

MS(ESI) m/z 552 (M+H)+

Step 3. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}-N-propylglycinehydrochloride (compound 10)

N-{3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}-N-allylglycinebenzyl ester trifluoroacetic acid salt (1.94 g, 2.91 mmol) was dissolvedin ethanol (40 mL) and water (10 mL), palladium hydroxide (0.4 g) wasadded, and the mixture was stirred at room temperature for 6 hours undera hydrogen atmosphere. The reaction mixture was filtered through celite,and the filtrate was concentrated under reduced pressure. To theobtained residue was added 0.01N-hydrochloric acid solution (250 mL),and the mixture was lyophilized to give the title compound (1.19 g, 2.02mmol, 70%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.05 (2H, br s), 7.93 (2H,m), 7.74 (2H, m), 7.11 (1H, d, J=3.6 Hz), 3.75-3.65 (2H, m), 3.18 (2H,s), 1.58-1.48 (2H, m), 1.25 (6H, br s), 0.84 (3H, m).

MS(ESI) m/z 464 (M+H)+

Example 5 Synthesis of3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoicacid trifluoroacetic acid salt (compound 18) Step 1. Synthesis of2-(diethylphosphono)butyric acid methyl ester

Methyl 2-bromobutanoate (92 g, 0.508 mol) and triethylphosphite (95 g,0.57 mol) were mixed, and the mixture was stirred at 110° C. for 3 days.The reaction mixture was dried under reduced pressure to give the titlecompound.

¹H-NMR (400 MHz, CDCl₃) δ 4.20-4.05 (4H, m), 3.76 (3H, s), 2.88 (1H,ddd, J=22.4, 10.4, 4.0 Hz), 2.18-1.98 (2H, m), 1.35-1.30 (6H, m), 1.19(3H, t, J=8.0 Hz).

Step 2. Synthesis of5-[(1E)-2-(methoxycarbonyl)-but-1-en-1-yl]thiophene-2-carboxylic acidtert-butyl ester

2-(Diethylphosphono)butyric acid methyl ester (46 g, 0.193 mol) wasdissolved in tetrahydrofuran (300 mL), 60% sodium hydride (6.6 g, 0.165mol) was added at 0° C., and the mixture was stirred for 30 minutes. Tothe reaction mixture was added a solution of5-formyl-2-thiophenecarboxylic acid tert-butyl ester obtained in Example1, step 2 (32.1 g, 0.15 mol) in tetrahydrofuran (10 mL), and the mixturewas stirred at room temperature for 2 hours. The solvent was evaporated,and the residue was partitioned between ethyl acetate and1N-hydrochloric acid solution, and washed successively with water andbrine. After drying over anhydrous magnesium sulfate, the residue waspurified by silica gel column chromatography to give the title compound(35.6 g, 0.12 mol, 80%).

¹H-NMR (400 MHz, CDCl₃) δ 7.71 (1H, s), 7.65 (1H, d, J=4.0 Hz), 7.17(1H, d, J=4.0 Hz), 3.82 (3H, s), 2.73 (2H, q, J=7.6 Hz), 1.56 (9H, s),1.18 (3H, t, J=7.6 Hz).

Step 3. Synthesis of(E)-3-(5-tert-butoxycarbonylthiophen-2-yl)-2-ethylpropenoic acid

5-[(1E)-2-(Methoxycarbonyl)-but-1-en-1-yl]thiophene-2-carboxylic acidtert-butyl ester (34.6 g, 120 mol) was dissolved in tetrahydrofuran (150mL), and methanol (60 mL), 1 N lithium hydroxide solution (144 mL, 144mmol) was added, and the mixture was stirred at room temperature for 2days. The mixture was concentrated under reduced pressure. 0.5N-Hydrochloric acid solution and ethyl acetate were added to theobtained residue, the organic layer was separated, and the aqueous layerwas extracted three times with ethyl acetate.

The organic layers were combined, washed with brine, and dried overanhydrous magnesium sulfate. After filtration, the solvent of thefiltrate was evaporated under reduced pressure to give the titlecompound (32.2 g, 114 mmol, 95%).

¹H-NMR (400 MHz, CDCl₃) δ 7.82 (1H, s), 7.66 (1H, d, J=4.0 Hz), 7.21(1H, d, J=4.0 Hz), 2.74 (2H, q, J=7.6 Hz), 1.59 (9H, s), 1.21 (3H, t,J=7.6 Hz).

Step 4. Synthesis of2-((5-tert-butoxycarbonylthiophen-2-yl)methyl)butanoic acid

(E)-3-(5-tert-butoxycarbonylthiophen-2-yl)-2-ethylpropenoic acid (20.43g, 72.4 mmol) was dissolved in ethyl acetate (300 mL), methanol (20 mL)and chloroform (10 mL), palladium hydroxide (2.0 g) was added, and themixture was stirred at room temperature overnight under a hydrogenatmosphere. After completion of the reaction, palladium hydroxide wasremoved by celite filtration, and the solvent was evaporated underreduced pressure to give the title compound (20.6 g, quantitative).

Step 5. Synthesis of 5-(2-benzyloxycarbonylbutyl)thiophene-2-carboxylicacid tert-butyl ester

2-(5-tert-Butoxycarbonylthiophen-2-yl)methyl-butanoic acid (20.6 g, 72.2mmol) was dissolved in N,N-dimethylformamide (100 mL), potassiumcarbonate (10.4 g, 75.3 mmol) and benzyl bromide (13.0 g, 76.0 mmol)were added, and the mixture was stirred at room temperature overnight.The reaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. 0.5 N-Hydrochloric acid solutionand ethyl acetate were added to the obtained residue, the organic layerwas separated, and the aqueous layer was extracted three times withethyl acetate. The organic layers were combined, washed with brine, anddried over anhydrous magnesium sulfate. After filtration, the solvent ofthe filtrate was evaporated under reduced pressure. The obtained residuewas purified by silica gel column chromatography to give the titlecompound (27.0 g, 72.1 mmol, 96%).

¹H-NMR (400 MHz, CDCl₃) δ 7.49 (1H, d, J=3.6 Hz), 7.35-7.25 (5H, m),6.71 (1H, d, J=3.6 Hz), 5.11 (1H, d, J=12.4 Hz), 5.07 (1H, d, J=12.4Hz), 3.16 (1H, dd, J=14.8, 8.8 Hz), 2.96 (1H, dd, J=14.8, 6.0 Hz), 2.72(1H, m), 1.73-1.60 (2H, m), 1.56 (9H, s), 0.92 (3H, t, J=7.6 Hz).

Step 6. Synthesis of5-(2-benzyloxycarbonyl-2-ethylbutyl)thiophene-2-carboxylic acidtert-butyl ester

5-(2-Benzyloxycarbonylbutyl)thiophene-2-carboxylic acid tert-butyl ester(29.5 g, 78.8 mmol) was dissolved in tetrahydrofuran (200 mL), 1.09 Mlithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (94 mL, 102mmol) was added dropwise at −78° C., and the mixture was stirred for 2hours. To the reaction mixture was added ethyl iodide (12.3 g, 156 mmol)at −78° C., and the mixture was stirred at room temperature overnight.The reaction mixture was concentrated under reduced pressure. Theresidue was added to ethyl acetate and 0.5 N-hydrochloric acid solution,the organic layer was separated, and the aqueous layer was extracted twotimes with ethyl acetate. The organic layers were combined, washed withsodium thiosulfate solution and brine, and dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography to give thetitle compound (24.9 g, 61.9 mmol, 78%).

¹H-NMR (400 MHz, CDCl₃) δ 7.49 (1H, d, J=4.0 Hz), 7.40-7.30 (5H, m),6.67 (1H, d, J=4.0 Hz), 5.15 (2H, s), 3.11 (2H, s), 1.70-1.59 (4H, m),1.56 (9H, s), 0.85 (6H, t, J=7.6 Hz).

Step 7. Synthesis of5-(2-benzyloxycarbonyl-2-ethyl-butyl)thiophene-2-carboxylic acid

To 5-(2-benzyloxycarbonyl-2-ethylbutyl)thiophene-2-carboxylic acidtert-butyl ester (24.9 g, 61.9 mmol) was added trifluoroacetic acid (20mL), and the mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated to give the title compound (quantitative).

Step 8. Synthesis of3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoicacid benzyl ester trifluoroacetic acid salt

5-(2-Benzyloxycarbonyl-2-ethyl-butyl)thiophene-2-carboxylic acid (5.0 g,14.4 mmol) was dissolved in N-methylpyrrolidone (5 mL), anddichloromethane (5 mL), thionylchloride (1.27 mL, 17.6 mmol) was addedat 0° C., and the mixture was stirred for 15 minutes at 0° C.3-fluoro-4-hydroxybenzamidine hydrochloride (2.7 g, 14.2 mmol) andpyridine (7 mL) were added to the reaction mixture, and the mixture wasstirred for 2 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure, and the obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(4.3 g, 7.21 mmol, 51%).

MS(ESI) m/z 483(M+H)+

Step 9. Synthesis of3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoicacid trifluoroacetic acid salt (compound 18)

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoicacid benzyl ester trifluoroacetic acid salt (4.3 g, 7.21 mmol) wasdissolved in 2-propanol (160 mL) and water (40 mL), palladium hydroxide(0.9 g) was added, and the mixture was stirred at room temperatureovernight under a hydrogen atmosphere. The reaction mixture was filteredthrough celite, and the filtrate was concentrated under reducedpressure. Water and acetonitrile was added to the residue, the mixturewas lyophilized to give the title compound (3.61 g, 7.12 mmol, 99%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.24 (2H, br s), 7.97 (1H,d, J=4.0 Hz), 7.94 (1H, d, J=10.4 Hz), 7.80-7.70 (2H, m), 7.10 (1H, d,J=4.0 Hz), 3.15 (2H, s), 1.60-1.40 (4H, m), 0.85 (6H, t, J=7.6 Hz).

MS(ESI) m/z 393(M+H)+

Example 6 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropionyl}-L-serinehydrochloride (compound 11)

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoicacid trifluoroacetic acid salt (compound 18) (616 mg, 1.2 mmol) wasdissolved in thionyl chloride (6 mL), and the mixture was stirred at 60°C. for 20 minutes. Thionyl chloride was evaporated under reducedpressure to give the acid chloride. The obtained acid chloride wasdissolved in dichloromethane (20 mL), O-tert-butyl-L-serine tert-butylester hydrochloride (334 mg, 1.32 mmol.) and pyridine (0.5 mL) wereadded thereto, and the mixture was stirred at room temperatureovernight. After evaporation of the solvent, trifluoroacetic acid (5 mL)was added, and the mixture was stirred at room temperature for 30minutes. The mixture was concentrated under reduced pressure. Theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe trifluoroacetic acid salt of the title compound.

To the obtained trifluoroacetic acid salt was added 0.05 N-hydrochloricacid solution (30 mL), and the mixture was lyophilized to give the titlecompound (513 mg, 0.99 mmol, 83%).

¹H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.95-7.90(2H, m), 7.78-7.72 (2H, m), 7.63 (1H, d, J=7.6 Hz), 7.10 (1H, d, J=4.0Hz), 4.34 (1H, m), 3.75-3.64 (1H, m), 3.64-3.56 (1H, m), 3.16 (2H, s),1.62-1.46 (4H, m), 0.88-0.78 (6H, m).

MS(ESI) m/z 480 (M+H)+

Example 7 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropionyl}-sarcosinehydrochloride (compound 21) Step 1. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropionyl}-sarcosinebenzyl ester trifluoroacetic acid salt

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoicacid trifluoroacetic acid salt (compound 18) (100 mg, 0.20 mmol) wasdissolved in thionyl chloride (2 mL), and the mixture was stirred atroom temperature for 30 minutes. Thionyl chloride was evaporated underreduced pressure to give the acid chloride. The obtained acid chloridewas dissolved in 1,2-dichloroethane (5 mL), sarcosine benzyl esterhydrochloride (47 mg, 0.22 mmol) and pyridine (0.2 mL) were addedthereto, and the mixture was stirred at 60° C. for 5 hours. The mixturewas concentrated under reduced pressure. The obtained residue waspurified by high performance liquid chromatography (water-acetonitrile,each containing 0.1% trifluoroacetic acid) to give the title compound(83 mg, 0.12 mmol, 62%).

Step 2. Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropionyl}-sarcosinehydrochloride (compound 21)

N-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropionyl}-sarcosinebenzyl ester trifluoroacetic acid salt (83 mg, 0.12 mmol) was dissolvedin 2-propanol (5 mL) and water (5 mL), palladium hydroxide (50 mg) wasadded, and the mixture was stirred at room temperature for 2 hours undera hydrogen atmosphere. The mixture was concentrated under reducedpressure. The obtained residue was purified by high performance liquidchromatography (water-acetonitrile, each containing 0.1% trifluoroaceticacid) to give the trifluoroacetic acid salt of the title compound. Tothe obtained trifluoroacetic acid salt were added 0.01N-hydrochloricacid solution (30 mL), and the mixture was lyophilized to give the titlecompound (32 mg, 0.064 mmol, 53%).

1H-NMR (400 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.22 (2H, br s), 7.90-7.85(2H, m), 7.70-7.65 (2H, m), 7.06 (1H, d, J=3.6 Hz), 3.92 (2H, m), 3.15(3H, s), 3.12 (2H, br s), 1.70-1.60 (2H, m), 1.60-1.50 (2H, m), 0.76(6H, t, J=7.2 Hz).

MS(ESI) m/z 464 (M+H)+

Example 8 Synthesis ofN-allyl-N-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)-thiophen-2-yl]-2,2-dimethylpropionyl}taurine(compound 23) Step 1. Synthesis of N-allyltaurine isopropyl ester

2-Chloroethylsulfonyl chloride (2 g, 12.3 mmol) was is dissolved in2-propanol (20 mL), pyridine (2.7 mL) was added, and the mixture wasstirred at room temperature for 3 hours. Allylamine hydrochloride (1.15g, 12.3 mmol) and diisopropylethylamine (6.4 mL) was added, and stirredat room temperature for 3 hours. The reaction mixture was evaporatedunder reduced pressure, 5% sodium bicarbonate solution was added to theresidue, and the mixture was extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give the title compound (0.5 g,2.4 mmol, 20%).

¹H-NMR (400 MHz, CDCl₃) δ 6.55 (1H, dd, J=10.0, 16.8 Hz), 6.39 (1H, d,J=16.8 Hz), 6.07 (1H, d, J=10.0 Hz), 4.81 (1H, sep, J=6.3 Hz), 1.40 (6H,d, J=6.3 Hz).

MS(ESI) m/z 208 (M+H)+

Step 2. Synthesis ofN-allyl-N-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropionyl}taurine(compound 23)

3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-dimethylpropanoicacid trifluoroacetic acid salt (200 mg, 0.40 mmol) obtained in Example3, step 5 was dissolved in thionyl chloride (4 mL), and the mixture wasstirred at room temperature for 30 minutes. Thionyl chloride wasevaporated under reduced pressure to give the acid chloride. Theobtained acid chloride was dissolved in 1,2-dichloroethane (10 mL),N-allyltaurine isopropyl ester obtained in step 1 (88 mg, 0.43 mmol) andpyridine (0.4 mL) were added thereto, and the mixture was stirred at 50°C. overnight. The mixture was concentrated under reduced pressure. Theobtained residue was purified by high performance liquid chromatography(water-acetonitrile, each containing 0.1% trifluoroacetic acid) to givethe isopropyl ester of the title compound. The obtained solid wasdissolved in 0.01 N aqueous hydrochloric acid (20 mL) solution andstirred at room temperature for 5 hours, and the precipitated solid wascollected by filtration. The solid was washed with water and dried togive the title compound (47 mg, 0.092 mmol, 23%).

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.02 (2H, br s), 7.95-7.88(2H, m), 7.81-7.70 (2H, m), 7.10 (1H, d, J=3.6 Hz), 5.76 (1H, m),5.20-5.05 (2H, m), 4.15-3.85 (2H, m), 3.70-3.45 (2H, m), 3.21 (2H, s),2.67 (2H, m), 1.26 (6H, s).

MS(ESI) m/z 512 (M+H)+

Example 9 Synthesis ofN-{3-[5-(4-amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropionyl}-beta-homoisoleucinehydrochloride (compound 49)

The compound 18 (76 mg, 0.15 mmol) was dissolved in thionyl chloride(1.5 mL), and the mixture was stirred at room temperature for 30minutes. Thionyl chloride was evaporated under reduced pressure to givethe acid chloride. The obtained acid chloride was dissolved indichloromethane (1.5 mL), beta-homoisoleucine methyl ester hydrochloride(44 mg, 0.225 mmol) and pyridine (0.2 mL) were added thereto, and themixture was stirred at room temperature overnight. After evaporation ofthe solvent, trifluoroacetic acid (5 mL) was added, and the mixture wasstirred at 60° C. for 1 hour. The mixture was concentrated under reducedpressure. After evaporation of the solvent, 4 N-hydrogen chloride in1,4-dioxane (2 mL) and water (1 mL) were added, and the mixture wasstirred at 80° C. 30 minutes. The mixture was concentrated under reducedpressure. The obtained residue was purified by high performance liquidchromatography (water-acetonitrile, each containing 0.1% trifluoroaceticacid) to give the trifluoroacetic acid salt of the title compound.

To the obtained trifluoroacetic acid salt was added 0.1 N-hydrochloricacid solution (10 mL), and the mixture was lyophilized to give the titlecompound (35.6 mg, 0.064 mmol, 43%).

1H NMR (400 MHz, DMSO-d6) δ 12.09 (1H, s), 9.44 (2H, s), 9.17 (2H, s),7.98-7.91 (2H, m), 7.78-7.72 (2H, m), 7.37 (1H, d, J=8.2 Hz), 7.06 (1H,d, J=3.8 Hz), 4.19-4.09 (1H, m), 3.17-3.06 (2H, m), 2.43-2.30 (2H, m),1.63-1.44 (4H, m), 1.40-1.27 (1H, m), 1.11-0.98 (1H, m), 0.89-0.73 (10H,m).

MS(ESI) m/z 520 (M+H)+

The compounds 39, 40, 45, 46, 51, 55, 63, 64, 65, 68, 81, and 89 shownin the following Table 1 were each synthesized using the compound 16 orthe compound obtained in Example 3, step 5 and commercially availablereagents and by an operation in the same manner as in theabove-mentioned Example 4, step 2.

The compounds 3, 4, 6, 12, 13, 14, 15, 16, 19, 24, 25, 27, 28, 29, 30,31, 34, 42, 43, 44, 52, 58, 83, and 87 shown in the following Table 1were each synthesized using the compound 16 or the compound obtained inExample 3, step 5 and commercially available reagents and by anoperation in the same manner as in the above-mentioned Example 6.

The compounds 7, 8, 17, 20, 22, 26, 32, 33, 41, 48, 56, 57, 62, 66, 67,69, 70, 71, 73, 75, 76, 77, 78, 79, 80, 84, 85, 86, 88, 90, 91, 92, and93 shown in the following Table 1 were each synthesized using thecompound 16 or the compound obtained in Example 3, step 5 andcommercially available reagents and by an operation in the same manneras in the above-mentioned Example 7.

The compounds 5, 35, 36, 37, 38, 47, 50, 53, 54, 59, 60, 61, 72, 74, 82,and 94 shown in the following Table 1 were each synthesized using thecompound 16 or the compound obtained in

Example 3, step 5 and commercially available reagents and by anoperation in the same manner as in the above-mentioned Example 9.

TABLE 1 Compound No. Structure Analysis data  1

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.09 (2H, br s), 8.07 (1H,d, J = 8.0 Hz), 7.99-7.83 (2H, m), 7.92-7.82 (1H, m), 7.79-7.69 (2H, m),7.06 (1H, d, J = 3.9 Hz), 4.56 (1H, dd, J = 13.9, 7.6 Hz), 3.48 (2H, s),2.74 (1H, dd, J = 16.4, 6.0 Hz), 2.64-2.49 (1H, m), 2.40-2.25 (2H, m),2.05-1.83 (3H, m), 1.80-1.69 (1H, m). MS (ESI) m/z 492 (M + H)+  2

1H-NMR (400 MHz, DMSO-d6) δ 9.36 (2H, br s), 9.08 (2H, br s), 7.97 (1H,d, J = 7.9 Hz), 7.89-7.80 (2H, m), 7.72-7.63 (2H, m), 7.00 (1H, d, J =3.9 Hz), 4.49 (2H, dt, J = 12.9, 6.4 Hz), 3.17 (2H, s), 2.69 (1H, dd, J= 16.4, 6.0 Hz), 2.57-2.45 (2H, m), 2.02-1.81 (2H, m), 1.63-1.37 (6H,m). MS (ESI) m/z 506 (M + H)+  3

1H NMR (400 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.17 (2H, br s), 8.12-7.98(1H, m), 7.98-7.87 (2H, m), 7.83-7.68 (2H, m), 7.08 (1H, d, J = 3.9 Hz),3.73 (2H, d, J = 5.8 Hz), 3.12 (2H, s), 1.13 (6H, s) MS (ESI) m/z 422(M + H)+  4

1H NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.07 (2H, br s), 7.98-7.87(2H, m), 7.82-7.69 (2H, m), 7.56 (1H, d, J = 7.8 Hz), 7.09 (1H, d, J=3.9 Hz), 4.30 (1H, dt, J = 7.9, 5.0 Hz), 3.70 (2H, ddd, J = 15.2, 11.1,4.9 Hz), 3.16 (2H, s), 1.17 (6H, s) MS (ESI) m/z 452 (M + H)+  5

MS (ESI) m/z 462 (M + H)+  6

1H NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.12 (2H, br s), 8.00-7.87(2H, m), 7.81- 7.68 (2H, m), 7.54 (1H, s), 7.08 (1H, d, J = 3.8 Hz),3.13 (2H, s), 1.36 (6H, s), 1.14 (6H, s) MS (ESI) m/z 450 (M + H)+  7

¹H NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.18 (2H, br s), 7.98-7.88(2H, m), 7.81- 7.70 (2H, m), 7.12 (1H, d, J = 3.8 Hz), 3.99 (3H, s),3.21 (2H, s), 1.26 (6H, s) MS (ESI) m/z 436 (M + H)+  8

MS (ESI) m/z 462 (M + H)+  9

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 8.00-7.89(2H, m), 7.80- 7.70 (2H, m), 7.57 (1H, d, J = 7.2 Hz), 7.08 (1H, s),4.13 (1H, m), 3.21 (1H, d, J = 16.0 Hz), 3.15 (1H, d, J = 16.0 Hz),2.15-2.05 (1H, m), 1.76- 1.50 (4H, m), 0.90 (3H, d, J = 6.8 Hz),0.86-0.75 (6H, m). MS (ESI) m/z 464 (M + H)+ 10

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.05 (2H, br s), 7.93 (2H,m), 7.74 (2H, m), 7.11 (1H, d, J = 3.6 Hz), 3.75-3.65 (2H, m), 3.18 (2H,s), 1.58-1.48 (2H, m), 1.25 (6H, br s), 0.84 (3H, m). MS (ESI) m/z 464(M + H)+ 11

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.95-7.90(2H, m), 7.78- 7.72 (2H, m), 7.63 (1H, d, J = 7.6 Hz), 7.10 (1H, d, J =4.0 Hz), 4.34 (1H, m), 3.75-3.64 (1H, m), 3.64-3.56 (1H, m), 3.16 (2H,s), 1.62-1.46 (4H, m), 0.88-0.78 (6H, m). MS (ESI) m/z 480 (M + H)+ 12

1H-NMR (400 MHz, DMSO-d6) δ 9.37 (4H, br s), 7.95-7.88 (2H, m),7.78-7.72 (2H, m), 7.56 (1H, d, J = 6.8 Hz), 7.10 (1H, d, J = 3.6 Hz),4.23 (1H, m), 3.72-3.68 (1H, m), 3.65-3.58 (1H, m), 3.16 (2H, s),1.62-1.49 (4H, m), 0.88-0.80 (6H, m). MS (ESI) m/z 480 (M + H)+ 13

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.95-7.88(2H, m), 7.80-7.70 (2H, m), 7.57 (1H, d, J = 7.2 Hz), 7.08 (1H, d, J =3.6 Hz), 4.13 (1H, m), 3.23-3.10 (2H, m), 2.08 (1H, m), 1.65-1.45 (4H,m), 0.90 (6H, d, J = 6.8 Hz), 0.88-0.80 (6H, m). MS (ESI) m/z 492 (M +H)+ 14

1H-NMR (400 MHz, DMSO-d6) δ 9.39 (2H, br s), 9.10 (2H, br s), 7.90-7.85(2H, m), 7.75- 7.65 (3H, m), 6.97 (1H, d, J = 2.4 Hz), 3.30 (2H, m),3.05 (2H, s), 2.35 (2H, t, J = 6.4 Hz), 1.50-1.30 (4H, m), 0.75-0.65(6H, t, J = 7.2 Hz). MS (ESI) m/z 464 (M + H)+ 15

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.18 (2H, br s), 7.95-7.90(2H, m), 7.78- 7.72 (2H, m), 7.18 (1H, d, J = 8.0 Hz), 7.10 (1H, d, J =4.0 Hz), 4.22 (1H, m), 4.12 (1H, m), 3.16 (2H, s), 1.62-1.49 (4H, m),1.03 (3H, d, J = 6.4 Hz), 0.88-0.80 (6H, t, J = 7.2 Hz). MS (ESI) m/z494 (M + H)+ 16

1H-NMR (400 MHz, DMSO-d6) δ 9.44 (4H, br s), 7.95 (1H, d, J = 11.2 Hz),7.88-7.80 (2H, m), 7.78-7.70 (2H, m), 7.30-7.20 (4H, m), 7.20- 7.12 (1H,m), 6.88 (1H, d, J = 4.0 Hz), 4.54 (1H, m), 3.18-2.92 (4H, m), 1.55-1.30(4H, m), 0.72 (3H, t, J = 7.2 Hz), 0.53 (3H, t, J = 7.2 Hz). MS (ESI)m/z 540 (M + H)+ 17

1H-NMR (400 MHz, DMSO-d6) δ 9.43 (2H, br s), 9.16 (2H, br s), 7.98-7.92(2H, m), 7.80- 7.70 (2H, m), 7.11 (1H, d, J = 4.0 Hz), 4.39 (1H, m),3.78-3.60 (2H, m), 3.24 (1H, d, J = 15.2 Hz), 3.16 (1H, d, J = 15.2 Hz),2.10 (1H, m), 2.00-1.85 (2H, m), 1.80-1.45 (5H, m), 0.88 (3H, t, J = 7.2Hz), 0.78 (3H, t, J = 7.2 Hz). MS (ESI) m/z 490 (M + H)+ 18

1H-NMR (400 MHz, DMSO-d6) δ 9.42 (2H, br s), 9.24 (2H, br s), 7.97 (1H,d, J = 4.0 Hz), 7.94 (1H, d, J = 10.4 Hz), 7.80-7.70 (2H, m), 7.10 (1H,d, J = 4.0 Hz), 3.15 (2H, s), 1.60-1.40 (4H, m), 0.85 (6H, t, J = 7.6Hz). MS (ESI) m/z 393 (M + H)+ 19

1H-NMR (400 MHz, DMSO-d6) δ 9.39 (2H, br s), 9.12 (2H, br s), 7.90-7.85(3H, m), 7.70- 7.65 (2H, m), 7.02 (1H, d, J = 4.0 Hz), 4.50 (1H, m),3.06 (2H, s), 2.70 (1H, dd, J = 16.4, 6.0 Hz), 2.51 (1H, dd, J = 16.4,7.2 Hz), 1.50-1.38 (4H, m), 0.80-0.70 (6H, m). MS (ESI) m/z 508 (M + H)+20

1H-NMR (400 MHz, DMSO-d6) δ 9.46 (4H, br s), 8.00-7.92 (2H, m),7.80-7.70 (2H, m), 7.13 (1H, d, J = 3.6 Hz), 3.89 (2H, m), 3.40 (2H, m),3.21 (2H, s), 1.80-1.40 (6H, m), 0.90-0.70 (9H, m). MS (ESI) m/z 492(M + H)+ 21

1H-NMR (400 MHz, DMSO-d6) δ 9.35 (2H, br s), 9.22 (2H, br s), 7.90-7.85(2H, m), 7.70- 7.65 (2H, m), 7.06 (1H, d, J = 3.6 Hz), 3.92 (2H, m),3.15 (3H, s), 3.12 (2H, br s), 1.70-1.60 (2H, m), 1.60-1.50 (2H, m),0.76 (6H, t, J = 7.2 Hz). MS (ESI) m/z 464 (M + H)+ 22

1H-NMR (400 MHz, DMSO-d6) δ 9.46 (2H, br s), 9.21 (2H, br s), 7.98-7.94(2H, m), 7.78- 7.74 (2H, m), 7.11 (1H, d, J = 3.6 Hz), 4.39 (1H, m),3.78-3.60 (2H, m), 3.24 (1H, d, J = 15.2 Hz), 3.16 (1H, d, J = 15.2 Hz),2.10 (1H, m), 2.00-1.85 (2H, m), 1.80-1.45 (5H, m), 0.88 (3H, t, J = 7.2Hz), 0.78 (3H, t, J = 7.2 Hz). MS (ESI) m/z 490 (M + H)+ 23

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.02 (2H, br s), 7.95-7.88(2H, m), 7.81- 7.70 (2H, m), 7.10 (1H, d, J = 3.6 Hz), 5.76 (1H, m),5.20-5.05 (2H, m), 4.15-3.85 (2H, m), 3.70- 3.45 (2H, m), 3.21 (2H, s),2.67 (2H, m), 1.26 (6H, s). MS (ESI) m/z 512 (M + H)+ 24

1H-NMR (400 MHz, DMSO-d6) δ 9.46 (2H, br s), 9.25 (2H, br s), 7.97-7.92(2H, m), 7.85 (1H, d, J = 7.2 Hz), 7.76-7.74 (2H, m), 7.08 (1H, d, J=3.6 Hz), 4.25 (1H, m), 3.15 (2H, s), 2.26 (2H, t, J = 8.0 Hz),2.06-1.95 (1H, m), 1.92-1.80 (1H, m), 1.60-1.46 (4H, m), 0.86-0.79 (6H,m). MS (ESI) m/z 528 (M + H)+ 25

1H-NMR (400 MHz, DMSO-d6) δ 9.45 (2H, br s), 9.16 (2H, br s), 7.97-7.92(3H, m), 7.78-7.72 (2H, m), 7.09 (1H, d, J = 3.6 Hz), 4.57 (1H, m), 3.13(2H, s), 2.76 (1H, dd, J = 16.4, 5.2 Hz), 2.58 (1H, dd, J = 16.4, 6.4Hz), 1.56-1.44 (4H, m), 0.86-0.78 (6H, m). MS (ESI) m/z 508 (M + H)+ 26

1H NMR (400 MHz, DMSO-d6) δ 9.45 (2H, br s), 9.18 (2H, br s), 7.99-7.88(2H, m), 7.80- 7.71 (2H, m), 7.09 (1H, d, J = 3.8 Hz), 4.20 (2H, d, J =13.7 Hz), 3.22 (2H, s), 3.06-2.91 (2H, m), 2.61-2.51 (1H, m), 1.93-1.77(2H, m), 1.50-1.35 (2H, m), 1.24 (6H, s) MS (ESI) m/z 476 (M + H)+ 27

MS (ESI) m/z 464 (M + H)+ 28

MS (ESI) m/z 478 (M + H)+ 29

MS (ESI) m/z 492 (M + H)+ 30

1H NMR (400 MHz, DMSO-d6) δ 12.05 (1H, s), 9.69-9.03 (4H, m), 7.94 (2H,t, J = 7.6 Hz), 7.80-7.71 (3H, m), 7.04 (1H, d, J = 3.9 Hz), 3.16-3.08(4H, m), 2.20 (2H, t, J = 7.4 Hz), 1.66 (2H, p, J = 7.2 Hz), 1.60-1.40(4H, m), 0.80 (6H, t, J = 7.4 Hz) MS (ESI) m/z 478 (M + H)+ 31

1H NMR (400 MHz, DMSO-d6) δ 9.71 (1H, s), 9.39 (2H, br s), 9.06 (2H, brs), 7.99-7.84 (4H, m), 7.84-7.76 (2H, m), 7.76-7.67 (2H, m), 7.07 (1H,d, J = 3.8 Hz), 3.34 (2H, s), 1.30 (6H, s) MS (ESI) m/z 484 (M + H)+ 32

1H NMR (400 MHz, DMSO-d6) δ 9.64 (1H, s), 9.40 (2H, br s), 9.07 (2H, brs), 8.25 (1H, s), 7.99-7.87 (3H, m), 7.79-7.69 (2H, m), 7.65 (1H, d, J =7.9 Hz), 7.44 (1H, dd, J = 7.9 Hz), 7.08 (1H, d, J = 3.5 Hz), 3.34 (2H,s), 1.29 (6H, s) MS (ESI) m/z 484 (M + H)+ 33

1H NMR (400 MHz, DMSO-d6) δ 12.54 (1H, s), 9.47 (2H, s), 9.21 (2H, s),7.95 (1H, d, J = 11.5 Hz), 7.92 (1H, d, J = 3.8 Hz), 7.81-7.69 (2H, m),7.08 (1H, d, J = 3.8 Hz), 3.89-3.33 (4H, m), 3.24-2.91 (3H, m),2.22-1.87 (2H, m), 1.22 (6H, s) MS (ESI) m/z 462 (M + H)+ 34

1H NMR (400 MHz, DMSO-d6) δ 9.46 (2H, s), 9.18 (2H, s), 8.20 (1H, d, J =6.0 Hz), 8.00- 7.91 (2H, m), 7.78-7.71 (2H, m), 7.06 (1H, d, J = 3.9Hz), 4.58-4.43 (2H, m), 4.07 (1H, dd, J = 9.1, 3.0 Hz), 3.15 (2H, s),2.87 (1H, dd, J = 17.7, 8.4 Hz), 2.45 (1H, dd, J = 17.7, 3.6 Hz),1.64-1.42 (4H, m), 0.86-0.76 (6H, m) MS (ESI) m/z 476 (M + H)+ 35

MS (ESI) m/z 504 (M + H)+ 36

MS (ESI) m/z 504 (M + H)+ 37

MS (ESI) m/z 498 (M + H)+ 38

MS (ESI) m/z 498 (M + H)+ 39

MS (ESI) m/z 441 (M + H)+ 40

MS (ESI) m/z 457 (M + H)+ 41

1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, br s), 9.67-9.09 (4H, m),8.00-7.89 (2H, m), 7.81- 7.70 (2H, m), 7.08 (1H, d, J = 3.8 Hz),4.33-4.21 (1H, m), 3.68-3.50 (2H, m), 3.27-3.09 (2H, m), 2.83-2.71 (1H,m), 2.26-2.12 (1H, m), 2.00-1.76 (3H, m), 1.67-1.54 (1H, m), 1.22 (6H,d, J = 7.2 Hz) MS (ESI) m/z 476 (M + H)+ 42

1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, br s), 9.67-9.09 (4H, m),8.00-7.89 (2H, m), 7.81-7.70 (2H, m), 7.08 (1H, d, J = 3.8 Hz), 4.33-4.21 (1H, m), 3.68-3.50 (2H, m), 3.27-3.09 (2H, m), 2.83-2.71 (1H, m),2.26-2.12 (1H, m), 2.00- 1.76 (3H, m), 1.67-1.54 (1H, m), 1.22 (6H, d, J= 7.2 Hz) MS (ESI) m/z 521 (M + H)+ 43

1H NMR (400 MHz, DMSO-d6) δ 12.36 (2H, br s), 9.46 (2H, s), 9.23 (2H,s), 7.98-7.91 (2H, m), 7.85 (1H, d, J = 7.5 Hz), 7.79-7.72 (2H, m), 7.08(1H, d, J = 3.9 Hz), 4.29-4.20 (1H, m), 3.15 (2H, s), 2.27 (2H, t, J =7.6 Hz), 2.09- 1.80 (2H, m), 1.60-1.47 (4H, m), 0.89-0.78 (6H, m) MS(ESI) m/z 522 (M + H)+ 44

1H NMR (400 MHz, DMSO-d6) δ 12.54 (1H, s), 9.47 (2H, s), 9.21 (2H, s),7.98-7.89 (3H, m), 7.80-7.73 (2H, m), 7.38 (1H, s), 7.09 (1H, d, J = 3.9Hz), 6.92 (1H, s), 4.59 (1H, dd, J = 13.2, 7.4 Hz), 3.13 (2H, s),2.64-2.52 (2H, m), 1.57-1.44 (4H, m), 0.89-0.75 (6H, m) MS (ESI) m/z 507(M + H)+ 45

MS (ESI) m/z 471 (M + H)+ 46

MS (ESI) m/z 440 (M + H)+ 47

MS (ESI) m/z 500 (M + H)+ 48

1H NMR (400 MHz, DMSO-d6) δ 12.35 (1H, s), 9.50-9.17 (4H, m), 8.03-7.96(2H, m), 7.83- 7.77 (2H, m), 7.60 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J =8.0 Hz), 7.14 (1H, d, J = 8.0), 3.57 (2H, s), 3.34 (2H, s), 1.79-1.65(4H, m), 0.92 (6H, t, J = 8.0 Hz). MS (ESI) m/z 526 (M + H)+ 49

1H NMR (400 MHz, DMSO-d6) δ 12.09 (1H, s), 9.44 (2H, s), 9.17 (2H, s),7.98-7.91 (2H, m), 7.78-7.72 (2H, m), 7.37 (1H, d, J = 8.2 Hz), 7.06(1H, d, J = 3.8 Hz), 4.19-4.09 (1H, m), 3.17-3.06 (2H, m), 2.43-2.30(2H, m), 1.63-1.44 (4H, m), 1.40-1.27 (1H, m), 1.11-0.98 (1H, m),0.89-0.73 (10H, m) MS (ESI) m/z 520 (M + H)+ 50

1H NMR (400 MHz, DMSO-d6) δ 12.86 (1H, br s), 9.41 (2H, s), 9.14 (2H,s), 7.96-7.85 (3H, m), 7.77-7.70 (3H, m), 7.29 (1H, d, J = 8.0 Hz), 7.07(1H, d, J = 3.8 Hz), 4.82 (2H, s), 3.89-3.80 (2H, m), 2.93-2.85 (2H, m),1.30 (6H, s), 1.04 (2H, d, J = 6.1 Hz) MS (ESI) m/z 524 (M + H)+ 51

MS (ESI) m/z 471 (M + H)+ 52

1H NMR (400 MHz, DMSO-d6) δ 9.45 (2H, br s), 9.30 (2H, br s), 8.00-7.91(2H, m), 7.91- 7.82 (1H, m), 7.82-7.69 (2H, m), 7.04 (1H, d, J = 3.9Hz), 3.83-3.64 (1H, m), 3.19-3.04 (4H, m), 1.86-1.64 (2H, m), 1.64-1.37(4H, m), 0.80 (6H, t, J = 7.4 Hz) MS (ESI) m/z 507 (M + H)+ 53

MS (ESI) m/z 526 (M + H)+ 54

MS (ESI) m/z 434 (M + H)+ 55

MS (ESI) m/z 471 (M + H)+ 56

1H NMR (400 MHz, DMSO-d6) δ 9.31 (4H, br s), 8.09 (1H, s), 7.97-7.89(2H, m), 7.79- 7.70 (2H, m), 7.08 (1H, d, J = 3.9 Hz), 3.14 (2H, s),2.30-2.14 (2H, m), 1.88 (4H, dd, J = 14.5, 6.8 Hz), 1.15 (6H, s) MS(ESI) m/z 462 (M + H)+ 57

MS (ESI) m/z 448 (M + H)+ 58

MS (ESI) m/z 594 (M + H)+ 59

MS (ESI) m/z 528 (M + H)+ 60

MS (ESI) m/z 542 (M + H)+ 61

MS (ESI) m/z 434 (M + H)+ 62

1H NMR (400 MHz, DMSO-d6) δ 11.98 (1H, br s), 9.44 (2H, s), 9.18 (2H,s), 7.95-7.92 (2H, m), 7.78-7.69 (m, 3H), 7.04 (1H, d, J = 3.9 Hz),3.12-3.08 (4H, m), 2.20 (2H, t, J = 6.6 Hz), 1.59-1.40 (8H, m), 0.79(6H, t, J = 7.4 Hz). MS (ESI) m/z 492 (M + H)+ 63

MS (ESI) m/z 417 (M + H)+ 64

1H NMR (400 MHz, DMSO-d6) δ 9.47 (2H, s), 9.21 (2H, s), 7.98-7.86 (3H,m), 7.79-7.73 (2H, m), 6.99 (1H, d, J = 3.8 Hz), 3.46 (2H, dd, J = 12.8,7.1 Hz), 3.09 (2H, s), 3.05 (2H, t, J = 7.1 Hz), 1.10 (6H, s) MS (ESI)m/z 460 (M + H)+ 65

1H NMR (400 MHz, DMSO-d6) δ 9.45 (2H, s), 9.22 (2H, s), 8.50 (1H, t, J =5.5 Hz), 7.98- 7.92 (1H, m), 7.89 (1H, d, J = 3.8 Hz), 7.79- 7.73 (2H,m), 6.99 (1H, d, J = 3.8 Hz), 4.54 (2H, d, J = 5.6 Hz), 3.13 (2H, s),1.17 (6H, s) MS (ESI) m/z 446 (M + H)+ 66

1H NMR (400 MHz, DMSO-d6) δ 9.87 (1H, br s), 9.40 (2H, br s), 9.29 (2H,s), 8.54 (2H, d, J = 2.0 Hz), 8.19 (1H, t, J = 2.0 Hz), 7.96 (1H, d, J =4.0 Hz), 7.94-7.92 (1H, m), 7.91-7.89 (1H, m), 7.75-7.72 (2H, m), 7.09(1H, d, J = 4.0 Hz), 1.83-1.51 (4H, m), 0.87 (6H, t, J = 7.0 Hz) MS(ESI) m/z 556 (M + H)+ 67

MS (ESI) m/z 570 (M + H)+ 68

MS (ESI) m/z 528 (M + H)+ 69

1H NMR (400 MHz, DMSO-d6) δ 9.47-9.30 (4H, br), 7.95-7.78 (2H, m),7.71-7.63 (2H, m), 7.10 (2H, d, J = 9.0 Hz), 6.93 (1H, d, J = 4.0 Hz),6.64 (2H, d, J = 9.0 Hz), 5.11 (1H, s), 3.09 (3H, d, J = 2.0 Hz), 1.11(6H, d, J = 6.0 Hz) MS (ESI) m/z 514 (M + H)+ 70

MS (ESI) m/z 490 (M + H)+ 71

MS (ESI) m/z 506 (M + H)+ 72

1H NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.17 (2H, s), 7.98-7.89 (2H,m), 7.81-7.70 (2H, m), 7.08 (1H, d, J = 4.0 Hz), 4.64-4.18 (2H, m),4.11-3.79 (2H, m), 3.10 (2H, s), 1.15 (6H, s) MS (ESI) m/z 448 (M + H)+73

MS (ESI) m/z 484 (M + H)+ 74

MS (ESI) m/z 500 (M + H)+ 75

MS (ESI) m/z 528 (M + H)+ 76

MS (ESI) m/z 476 (M + H)+ 77

MS (ESI) m/z 507 (M + H)+ 78

MS (ESI) m/z 490 (M + H)+ 79

MS (ESI) m/z 476 (M + H)+ 80

MS (ESI) m/z 490 (M + H)+ 81

1H NMR (400 MHz, DMSO-d6) δ 9.47 (1H, s), 9.21 (1H, s), 8.57 (1H, s),7.95 (1H, d, J = 11.6 Hz), 7.89 (1H, d, J = 3.8 Hz), 7.80-7.72 (1H, m),7.00 (1H, d, J = 3.8 Hz), 7.00 (1H, d, J = 3.8 Hz), 4.55 (1H, d, J = 5.5Hz), 3.14 (1H, s), 1.62-1.42 (1H, m), 0.78 (1H, t, J = 7.4 Hz) MS (ESI)m/z 474 (M + H)+ 82

MS (ESI) m/z 528 (M + H)+ 83

MS (ESI) m/z 450 (M + H)+ 84

1H NMR (400 MHz, DMSO-d6) δ 9.46 (2H, s), 9.18 (2H, s), 8.27 (1H, d, J =7.6 Hz), 7.97- 7.92 (1H, m), 7.87 (1H, d, J = 3.8 Hz), 7.79- 7.73 (2H,m), 6.98 (1H, d, J = 3.8 Hz), 5.29 (1H, dd, J = 14.4, 8.1 Hz), 3.20-3.09(2H, m), 2.36-2.06 (4H, m), 1.61-1.48 (4H, m), 0.77 (6H, dt, J = 20.1,7.4 Hz) MS (ESI) m/z 546 (M + H)+ 85

MS (ESI) m/z 490 (M + H)+ 86

1H NMR (400 MHz, DMSO-d6) δ 9.41 (2H, s), 9.16 (2H, s), 8.11 (1H, d, J =8.1 Hz), 7.96- 7.85 (2H, m), 7.81-7.70 (2H, m), 6.98 (1H, d, J = 3.9Hz), 4.88-4.78 (1H, m), 3.46-3.26 (2H, m), 3.08 (2H, s), 1.55-1.33 (4H,m), 0.75 (3H, t, J = 7.4 Hz), 0.65 (3H, t, J = 7.4 Hz) MS (ESI) m/z 532(M + H)+ 87

1H-NMR (400 MHz, DMSO-d6) δ 9.41 (2H, br s), 9.10 (2H, br s), 7.96 (1H,d, J = 4.0 Hz), 7.93 (1H, d, J = 8.1 Hz), 7.80-7.70 (2H, m), 7.09 (1H,d, J = 4.0 Hz), 3.14 (2H, s), 1.16 (6H, s). MS (ESI) m/z 365 (M + H)+ 88

1H NMR (400 MHz, DMSO-d6) δ 9.43 (2H, s), 9.21 (2H, s), 8.01-7.89 (2H,m), 7.83-7.70 (2H, m), 7.09 (1H, d, J = 3.8 Hz), 4.62-4.41 (1H, m),4.41-4.21 (2H, m), 4.21-3.98 (2H, m), 3.98-3.80 (1H, m), 3.46-3.35 (1H,m), 3.12 (2H, s), 1.62-1.39 (4H, m), 0.83 (6H, t, J = 7.4 Hz). MS (ESI)m/z 476 (M + H)+ 89

1H-NMR (400 MHz, DMSO-d6) δ 9.55 (1H, s), 9.41 (2H, s), 9.03 (2H, s),7.97-7.82 (3H, m), 7.82-7.65 (3H, m), 7.34-7.20 (2H, m), 7.08 (1H, d, J= 3.9 Hz), 3.30 (2H, s), 1.79-1.56 (4H, m), 0.85 (6H, t, J = 7.3 Hz). MS(ESI) m/z 548 (M + H)+ 90

1H-NMR (400 MHz, DMSO-d6) δ 9.80 (1H, s), 9.41 (2H, s), 9.07 (2H, s),8.58 (1H, d, J = 4.8 Hz), 8.15 (1H, s), 7.98-7.88 (3H, m), 7.82-7.66(2H, m), 7.08 (1H, d, J = 3.9 Hz), 3.3-3.25 (2H, m), 1.86-1.57 (4H, m),0.85 (6H, t, J = 7.3 Hz). MS (ESI) m/z 556 (M + H)+ 91

1H-NMR (400 MHz, DMSO-d6) δ 12.52 (1H, s), 9.44 (2H, s), 9.16 (2H, s),7.99-7.89 (2H, m), 7.80-7.71 (2H, m), 7.08 (1H, d, J = 3.8 Hz),3.81-3.53 (4H, m), 3.19 (2H, m), 3.10-2.90 (1H, m), 2.25-1.85 (2H, m),1.22 (6H, s). MS (ESI) m/z 462 (M + H)+ 92

1H-NMR (400 MHz, DMSO-d6) δ 9.46 (1H, s), 9.41 (2H, s), 9.10 (2H, s),8.06 (1H, d, J = 7.2 Hz), 7.96-7.90 (1H, m), 7.89 (1H, d, J = 3.8 Hz),7.81-7.69 (2H, m), 7.20 (2H, d, J = 8.6 Hz), 7.01 (1H, d, J = 3.8 Hz),6.73 (2H, d, J = 8.6 Hz), 5.26 (1H, d, J = 7.1 Hz), 3.17 (2H, s), 1.17(6H, s). MS (ESI) m/z 514 (M + H)+ 93

1H-NMR (400 MHz, DMSO-d6) δ 9.44 (2H, s), 9.14 (2H, s), 7.97-7.87 (2H,m), 7.80- 7.70 (2H, m), 7.13 (1H, d, J = 3.8 Hz), 5.18 (1H, m),4.40-4.27 (2H, m), 3.77- 3.63 (2H, m), 3.25 (1H, d, J = 14.1 Hz), 3.10(1H, d, J = 14.2 Hz), 2.11-2.00 (1H, m), 1.87-1.75 (1H, m), 1.22 (6H,s). MS (ESI) m/z 478 (M + H)+ 94

1H-NMR (400 MHz, DMSO-d6) δ 9.44 (2H, s), 9.14 (2H, s), 7.98-7.90 (2H,m), 7.80-7.70 (2H, m), 7.13-7.01 (2H, m), 5.68-5.61 (1H, m), 5.61-5.54(1H, m), 4.25-4.13 (1H, m), 3.21- 3.06 (2H, m), 2.82-2.73 (1H, m),2.48-2.38 (1H, m), 2.32-2.12 (3H, m), 1.14 (6H, d, J = 5.2 Hz). MS (ESI)m/z 488 (M + H)+

Experimental Example 1 Measurement of Trypsin Inhibitory Activity

Using a 96 well plate (#3915, Costar), a test compound (25 μL) was mixedwith 20 μM fluorescence enzyme substrate (Boc-Phe-Ser-Arg-AMC, 50 μL)mixed with 200 mM Tris-HCl buffer (pH 8.0), and human trypsin (Sigma, 25μL) was added. Using a fluorescence plate reader fmax (MolecularDevices, Inc.), the reaction rate was measured from the time-coursechanges at excitation wavelength 355 nm and fluorescence wavelength 460nm. The Ki value was calculated from the concentration of the testcompound, reciprocal of reaction rate, and Km value of the enzymesubstrate, and by using Dixon plot. The results are shown in Table 2.

Experimental Example 2 Measurement of Enteropeptidase InhibitoryActivity

Using a 96 well plate (#3915, Costar), a test compound (25 μL), 400 mMTris-HCl buffer (pH 8.0, 25 μL) and 0.5 mg/mL, fluorescence enzymesubstrate (Gly-Asp-Asp-Asp-Asp-Lys-β-Naphtylamide, 25 μL) were mixed,and recombinant human enteropeptidase (R&D Systems, Inc., 25 μL) wasadded. Using a fluorescence plate reader fmax (Molecular Devices, Inc.),the reaction rate was measured from the time-course changes atexcitation wavelength 320 nm and fluorescence wavelength 405 nm. The Kivalue was calculated from the concentration of the test compound,reciprocal of reaction rate, and Km value of the enzyme substrate, andby using Dixon plot. The results are shown in Table 2.

TABLE 2 Enteropeptidase Trypsin Compound inhibitory activity inhibitoryactivity No. Ki (nM) Ki (nM) 1 0.14 0.61 2 0.73 4.10 3 0.29 0.42 4 0.460.75 5 0.24 0.50 6 0.69 0.95 7 0.41 1.33 8 0.87 1.69 9 0.79 2.02 10 0.491.50 11 0.41 1.87 12 0.94 1.78 13 1.56 5.18 14 0.99 2.50 15 0.84 1.74 161.10 8.30 17 1.69 6.38 18 1.24 2.49 19 0.33 0.82 20 2.61 7.91 21 0.881.76 22 1.00 3.57 23 1.81 3.17 24 0.27 2.01 25 0.26 1.04 26 1.33 3.10 270.73 1.67 28 0.65 1.93 29 1.18 3.84 30 0.94 2.73 31 1.08 2.89 32 1.430.70 33 1.02 2.00 34 2.56 2.73 35 2.56 3.04 36 4.70 3.07 37 0.96 1.51 380.97 1.45 39 7.56 3.60 40 6.66 4.54 41 1.58 3.88 42 1.69 3.88 43 0.421.96 44 0.67 1.69 45 4.13 3.36 46 5.27 3.89 47 0.53 0.92 48 2.41 3.35 493.26 1.97 50 3.46 3.49 51 3.75 1.87 52 5.53 5.78 53 2.69 9.27 54 1.761.53 55 2.51 3.30 56 0.51 1.49 57 0.67 1.01 58 0.71 1.59 59 0.31 0.49 601.22 1.02 61 1.13 0.96 62 0.98 5.17 63 2.90 3.65 64 0.53 1.60 65 0.530.75 66 0.71 1.58 67 3.73 4.40 68 0.24 0.21 69 0.72 1.14 70 1.11 1.70 714.97 8.01 72 0.63 1.85 73 2.41 3.65 74 0.58 0.18 75 0.39 3.72 76 0.672.01 77 0.69 1.42 78 1.53 2.57 79 1.12 2.19 80 1.33 4.67 81 1.20 3.54 823.52 5.32 83 0.72 1.42 84 0.43 3.27 85 0.81 0.69 86 0.24 3.40 87 0.391.30 88 1.00 2.87 89 0.84 1.17 90 0.55 1.70 91 0.90 1.33 92 0.67 0.96 930.30 0.90 94 1.30 1.98

Thus, the compound of the present invention was confirmed to showsuperior enteropeptidase inhibitory activity and superior trypsininhibitory activity. Therefore, it has been shown that the compound ofthe present invention having an inhibitory activity on enteropeptidaseand trypsin decreases digestive capacity for protein, lipid, andcarbohydrates, and is effective as a therapeutic or prophylactic drugfor obesity and hyperlipidemia.

Experimental Example 3 Evaluation of Anti-Diabetic Action

Anti-diabetic action of the compound or pharmaceutical salt thereof ofthe present invention can be confirmed by, for example, the followingprocedure:

KK-A^(y)/JCL mice (male, 5-7 week-old, CLEA Japan, Inc.) known tospontaneously develop obese type 2 diabetes are purchased and, after oneweek of preliminary rearing period, randomly assigned to the groups (6per group) with the body weight and non-fasting blood glucose levels asindices. The animals are individually housed in a polycarbonate cage andallowed to drink water freely from a watering bottle. During the testperiod, they are allowed to freely ingest a mixture of a test compound,which may be in salt form thereof (5.6 mg/100 g or 16.8 mg/100 g, forexample) and powder feed CRF-1 (Oriental Yeast Co., Ltd.). CRF-1 aloneis given to the control group. After one week of dosing period, anaspirate of the blood (6 μL) is collected from the tail vein, and theblood glucose level is determined by ACCU-CHEK Aviva (Roche DiagnosticsK.K.).

Experimental Example 4 Evaluation of Hypoglycemic Action

Hypoglycemic action of some compounds was confirmed by, for example, thefollowing procedure:

Zucker Fatty rats (male, 11-19 week-old, Charles River Japan, Inc.)known to spontaneously develop hyperglycemia were randomly assigned tothe groups (6 per group). The animals were individually housed in apolycarbonate cage and allowed to drink water freely from a wateringbottle. The animals in the compound groups were gavaged with compoundNo. 10, 87, 19, or 69 at the dose of 3 mg/kg. These compounds were usedas HCl salt form thereof, converted by the method according to Example3, step 6 from TFA salt form thereof upon the necessity. The animals inthe control group were only treated with the vehicle (0.5%methylcellulose). Animals were allowed free access to the feed (CRF-1,Oriental Yeast Co., Ltd.) during the experiment. An aspirate of theblood (6 μL) was collected from the tail vein on the time point ofimmediately before dosing (time 0) as well as 2, 4, and 8 hours afterdosing. The blood glucose levels were determined with ACCU-CHEK Aviva(Roche Diagnostics K.K.). Serial changes of blood glucose levels in theanimals were shown in FIGS. 1 and 2. The blood glucose levels in thecompound group were significantly decreased comparing with those in thevehicle group 2 or 4 hours after dosing.

Thus, the test compounds were confirmed to show a significanthypoglycemic action. The compound of the present invention having anenteropeptidase inhibitory activity and a trypsin inhibitory activity isshown to have a blood glucose elevation suppressing action orhypoglycemic action. In addition, it can also be shown that the compoundof the present invention shows an insulin sensitizing activity and isalso useful as a prophylactic or therapeutic agent for obesity, diabeticcomplications, or metabolic syndrome, since it shows a blood glucoseelevation suppressing action or hypoglycemic action.

INDUSTRIAL APPLICABILITY

The trypsin and enteropeptidase inhibitory compound of the presentinvention can be used as an active ingredient of a therapeutic orprophylactic drug of diabetes or diabetic complications.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1. A method for treating hyperglycemia or diabetes, comprisingadministering an effective amount of a compound represented by formula(I):

wherein: R¹ and R² are the same or different and each is independently aC₁₋₄ alkyl group or a C₂₋₄ alkenyl group, or R¹ and R² together with thecarbon atom to which they are bonded form a C₃₋₈ cycloalkane ring; X is—OR³, —NR⁴R⁵ or a group represented by formula (II):

wherein: R³ is a hydrogen atom or a C₁₋₄ alkyl group; R⁴, R⁵ and R⁶ arethe same or different and each is independently a hydrogen atom, a C₁₋₈alkyl group, a carboxyl C₁₋₈ alkyl group or a C₃₋₈ alkenyl group, or R⁴and R⁵ together with the nitrogen atom to which they are bonded form aC₃₋₉ heterocycle, wherein said C₁₋₈ alkyl group, said C₃₋₈ alkenyl groupand said C₃₋₉ heterocycle may be substituted with one or moresubstituents; Ra and Rb are the same or different and each isindependently a hydrogen atom, a C₁₋₈ alkyl group, a carboxyl C₁₋₈ alkylgroup, a carboxyl group, an aryl group, a C₃₋₆ heterocyclic groupcontaining 1 to 4 heteroatoms selected from the group consisting of O, Nand S, or a C₃₋₈ cycloalkyl group, or Ra and Rb together with theatom(s) to which they are bonded form a C₃₋₈ cycloalkane ring or a C₃₋₉heterocycle containing 1-4 heteroatoms selected from the groupconsisting of O, N and S, wherein said C₁₋₈ alkyl group, said arylgroup, said C₃₋₈ cycloalkyl group, said C₃₋₈ cycloalkane ring and saidC₃₋₉ heterocycle may be substituted with one or more substituents; RingA is an arene, a C₃₋₆ heterocycle containing 1-4 heteroatoms selectedfrom the group consisting of O, N and S, or a C₃₋₈ cycloalkane ring; Yais a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group,a carbonyl group, a carboxyl C₁₋₃ alkyl group or a sulfo group; Yb is ahydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group, acarbonyl group, a carboxyl C₁₋₃ alkyl group, a nitro group, a cyanogroup or a C₁₋₃ alkoxyl group; p is 0, 1, 2, 3 or 4; q is 0 or 1; and R⁷is a hydrogen atom, a halogen atom or a nitro group; with the provisothat when R¹ and R² are both methyl groups, then neither of R⁴ nor R⁵ isan ethyl group substituted with two carboxyl groups, and when R¹ and R²are both methyl groups, then the group represented by formula (II) isnot a group represented by formula:

or a pharmaceutically acceptable salt thereof, to a subject in needthereof.
 2. A method according to claim 1, wherein X is —NR⁴R⁵ or agroup represented by formula (II), wherein R⁴, R⁵ and R⁶ are eachindependently a hydrogen atom or a C₁₋₈ alkyl group.
 3. A methodaccording to claim 1, wherein X is —NR⁴R⁵, wherein R⁴ and R⁵ togetherwith the nitrogen atom to which they are bonded form a C₃₋₉ heterocyclesubstituted by a hydrogen atom, a halogen atom, a carboxyl group, acarboxyl C₁₋₃ alkyl group or a hydroxyl group.
 4. A method according toclaim 1, wherein X is a group represented by formula (II), wherein p=1or 2, and q=0.
 5. A method according to claim 1, wherein X is a grouprepresented by formula (II), wherein p=0 and q=1.
 6. A method accordingto claim 1, wherein X is a group represented by formula (II), whereinp=1, q=1, and Ra and Rb are the same or different and each isindependently a hydrogen atom or a C₁₋₈ alkyl group, or Ra and Rbtogether with the atom(s) to which they are bonded form a C₃₋₈cycloalkane ring, wherein said C₁₋₈ alkyl group and said C₃₋₈cycloalkane ring may substituted with a group selected from the groupconsisting of a hydrogen atom, a carboxyl group, a carbamoyl group, ahydroxyl group, a phenyl group and a C₃₋₈ cycloalkyl group.
 7. A methodaccording to claim 1, wherein R¹ and R² are the same or different andeach is independently a methyl group, an ethyl group or a propyl group,or R¹ and R² together with the carbon atom to which they are bonded forma cyclobutane ring or a cyclopentane ring.
 8. A method according toclaim 1, wherein X is a group represented by formula (II), wherein q=1,and Ring A is a benzene ring, a pyridine ring, or a C₁₋₆ heterocyclecontaining 1-4 oxygen atoms.
 9. A method according to claim 1, wherein Xis a group represented by formula (II), wherein q=1, Ya is a halogenatom, a carboxyl group, a carboxyl C₁₋₃ alkyl group, a hydroxyl group, asulfo group or a carbonyl group, and Yb is a hydrogen atom, a halogenatom, a carboxyl group or a hydroxyl group.
 10. A method according toclaim 1, wherein X is —NR⁴R⁵, wherein when R⁴ or R⁵ has substituent(s),said substituent is selected from the group consisting of a halogenatom, a carboxyl group, a hydroxyl group, a carboxyl C₁₋₃ alkyl group, aC₃₋₈ alkenyl group, a carbamoyl group, a phenyl group, an amino group, asulfo group, a cyano group, a C₃₋₈ cycloalkyl group, and a C₁₋₈heterocyclic group containing 1 to 4 heteroatoms selected from the groupconsisting of O, N and S.
 11. A method according to claim 1, wherein Xis a group represented by formula (II), wherein, when Ra or Rb hassubstituent(s), said substituent is selected from the group consistingof a carboxyl group, a hydroxyl group, a phenyl group, an amino group, amethylthio group, a thiol group, a carbamoyl group, a guanidino group, aC₃₋₈ cycloalkyl group, and a C₁₋₈ heterocyclic group containing 1-4heteroatoms selected from the group consisting of O, N and S.
 12. Amethod according to claim 1, wherein, said compound represented byformula (I) is a compound represented by any of the following formulae:


13. A method according to claim 1, wherein said compound represented byformula (I) is a compound represented by any of the following formulae: